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Medicine » Cardiology and Cardiovascular Medicine » "Renin-Angiotensin System - Past, Present and Future", book edited by Anna Naidenova Tolekova, ISBN 978-953-51-3352-0, Print ISBN 978-953-51-3351-3, Published: July 12, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 2

Involvement of the Renin‐Angiotensin System in Atherosclerosis

By Ana Kolakovic, Maja Zivkovic and Aleksandra Stankovic
DOI: 10.5772/67137

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Involvement of the Renin‐Angiotensin System in Atherosclerosis

Ana Kolakovic, Maja Zivkovic and Aleksandra Stankovic
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The renin-angiotensin system (RAS) is a well known for its role in the regulation of the blood pressure (BP). Angiotensin II (Ang II), the main mediator of the RAS, may act either, as a systemic molecule or a locally produced factor. Within the vessel wall it has significant proinflammatory role by inducing the oxidative stress, secretion of inflammatory cytokines and adhesion molecules. Ang II could trigger proliferation of vascular smooth muscle cells (VSMC) and its migration to the outer layer of the vessel wall. It could induce the release of matrix metalloproteinase (MMPs), from human VSMC and thus increase susceptibility to rupture of atherosclerotic lesions. Binding of Ang II to AT1R/AT2R could have opposing actions in vascular injury. The ACE2/Ang (1-7)/Mas axis of the RAS also opposes the unfavourable actions of ACE/Ang II/ATR1 axis. Inhibition of RAS could reduce inflammation-associated processes in vasculature, independently of lowering BP. RAS is significantly modulated by the genes coding for this system. Certain genetic variants (SNPs) in the RAS genes have been denoted as the functional ones and have been associated with hypertension, cardiovascular phenotypes and atherosclerosis. Also, the genetic components of the RAS interfere with the regulators of gene expression by microRNAs (miRs).

Keywords: renin‐angiotensin system, atherosclerosis, genetic variant, micro RNA gene expression

1. Introduction

1.1. Short overview of the RAS

The renin‐angiotensin system (RAS) is a cascade well known for its primary role in the regulation of blood pressure (BP) and sodium homeostasis. It has a significant role in regulating fluid and electrolyte balance by exerting its actions on the heart, blood vessels and kidneys.

The circulating RAS comprises liver‐secreted angiotensinogen (AGT) that is enzymatically converted into angiotensin I (Ang I) in the bloodstream by kidney‐derived renin. In the next step, Ang I is being converted by angiotensin‐converting enzyme (ACE) to form Ang II. Ang II is the main effector in this system that acts either as a systemic molecule or as a locally produced factor.

The RAS is probably one of the most investigated biological systems over past 30 years. Given its pleiotropic biological effects, it is expected. Its complexity underlies the fact that research involving RAS molecules and actions in health and disease is still very active and intriguing. In the past decade, a substantial expansion of our knowledge of the RAS was emerged. It is verified by newly discovered components. One of them is a homologue of ACE, angiotensin‐converting enzyme 2 (ACE2), which exerts a role as a negative regulator of the RAS [1] by cleaving Ang II to Ang‐(1–7) [2, 3]. Namely, Santos et al. demonstrated that Ang-(1-7) is the ligand for the G-protein-coupled receptor Mas, and that the ACE2?Ang-(1?7)?Mas axis is the counter-regulating of the actions of classical RAS [4, 5]. Also, a variety of biologically active peptides, novel components of the RAS have been found recently: proangiotensin‐12 (angiotensin‐(1–12)) [6], angiotensin A (Ang A) [7, 8] and alamandine [9, 10].

1.2. Tissue and intracellular RAS

Our knowledge of the RAS has undergone substantial revision in the past few years. The existence of local (tissue) RAS systems that are independent of those stimulated by the classical RAS made it evident that the RAS is more complex than originally thought [11]. In that way, RAS is experienced substantial conceptual changes. Local (tissue) RAS represents tissue‐based formation of angiotensin peptides that operate separately from the circulating RAS [12]. Tissue RAS systems are located in all major organs, including brain, heart, large blood vessels, adrenals and the kidneys [13]. Local RAS systems exert various actions depending on the type of cells involved and play crucial role in the maintenance of cellular homeostasis.

In order to identify a tissue‐specific RAS at least one of the following criteria have to be fulfil [14]: (1) mRNAs for all components required for biosynthesis of a biologically active Ang II are present, (2) a biologically active angiotensin peptide is synthesized, (3) receptors for the biologically active angiotensin peptide are present, (4) the biologically active angiotensin peptide in the tissue is regulated, independently of the circulating RAS and (5) reduction or elimination of the action of the angiotensin peptide produces a physiological response.

There are other components of local RAS that are contributing to tissue‐specific mechanisms of angiotensin peptide formation. They are participating in the progression of disease, or contrary, in mechanisms that protect from tissue injury [12]. These components include the (pro)renin receptor [15, 16], renin‐independent mechanisms of Ang peptide generation from Ang‐(1–12) [17, 18], intracellular RAS [19], previously mentioned ACE2/Ang-(1?7)/Mas receptor pathway [20] and they all may possess therapeutic potential.

Although different concepts of local RAS have been described, its key characteristic is a synthesis of AGT and enzymes, such as renin, that cleaves AGT to produce Ang I independently of the circulating RAS [12, 21, 22]. The presence of ACE, Ang II type 1 (AT1R) and type 2 (AT2R) receptors and Ang II in different cells supports the concept of local RAS [23]. The local RAS seems to be regulated independently from the circulating system in a specific manner depending on the cell type and extracellular stimulus [24]. Despite that it can interact with the circulating system and complement it.

Some of the attempts to define local RAS that are independent of the circulating RAS were made in animal models [12]. One of the approaches to studying the functional importance of locally synthesized RAS components is to demonstrate their targeted overexpression or deletion in specific tissues. The evidence shows that in most tissues, local RAS enhances the actions of circulating Ang II, which has important implications for the pathophysiology of cardiovascular diseases.

In addition to classical and local tissue RAS, there is an intracellular RAS. This system is characterized by the presence of a functionally active RAS within the cells that can intracellularly synthesize Ang II [19, 25]. This means that Ang II is involved not only in an endocrine but also is a paracrine and an intracrine signaling system within tissues [26]. For example, intracellular delivery of Ang II leads to increase in intracellular calcium, growth of vascular smooth muscle cells (VSMCs) and regulation of muscle tone [27, 28]. This suggests that the intracellular Ang II has different functions compared to extracellular Ang II.

2. RAS and atherosclerosis

2.1. Molecular processes in atherosclerosis through the prism of RAS actions

Ang II, the main effector peptide of RAS, participates in all phases of the atherogenesis. It is proposed that the activation of RAS, and particularly Ang II, is involved in the initiation and progression of atherosclerosis in the absence of hemodynamic influences [29, 30]. Moreover, activation of RAS in the vascular wall has important modulatory activities in the development of atherosclerotic plaques, by stimulating a series of coordinated cellular and molecular events observed in the lesions.

2.1.1. Role of RAS in atherosclerosis development

The initial steps of atherosclerosis include endothelial dysfunction, which allows the migration of inflammatory cells and lipid droplets into the damaged part of the vessel wall, where they accumulate and form a “fatty streak”. Oxidative stress is one of the main factors that promote vascular endothelial dysfunction. This is initial phase of vascular damage, when elevated levels of reactive oxygen species (ROS) that might be caused by Ang II induce impaired endothelial relaxation and vascular function [31]. ROS are free radicals involving oxygen, such as superoxide anions, hydroxyl radicals and hydrogen peroxide. These are mainly generated by mitochondria as by‐products of cellular metabolism in the vessel wall by all vascular cells, including endothelial cells, VSMCs and adventitial fibroblasts. However, the imbalance between ROS generation and antioxidant protection leads to a state of oxidative stress, which can have deleterious effects as it modulates numerous cell signaling pathways. This is manifested as increased expression of pro‐inflammatory genes, cell migration and proliferation, extracellular matrix production and apoptosis in the vessel wall, all of which play an important role in vascular injury [32]. RAS activates NAD(P)H oxidase by enhancing Ang II/AT1R signaling which leads to increase in ROS production in both vascular endothelial cells and VSMCs [33, 34]. Ang II may traffic to mitochondria and AT1R could be expressed on outer mitochondrial membranes [35]. This way Ang II may stimulate an increase in mitochondrial oxidative stress, thus leads to VCMC senescence. Also, mitochondria may endogenously produce Ang II [3638]. Several animal studies show that Ang II causes and contributes to aortic endothelial dysfunction [3941]. It promotes abnormal vasomotion, a procoagulant state and transmigration of inflammatory cells into the vessel wall [42]. Within the vessel wall, Ang II increases vascular permeability via activation of vascular cell adhesion molecule‐1 (VCAM‐1) [43], intercellular adhesion molecule (ICAM)‐1 [44], and endothelial growth factor (VEGF) [41, 42, 45, 46]. The key step in the formation of the initial lesion in atherosclerosis is the inflammation at the site of plaque formation caused by monocytes recruited from the blood stream by VCAM‐1 [47]. Additionally, Ang II stimulates apoptosis of endothelial cell and VSMCs [48, 49].

The next stage in fatty streak formation is oxidation of low density lipoprotein (ox‐LDL). Ox‐LDL has important atherogenic properties as it penetrates the endothelial layer and gets taken up by macrophages and VSMCs, which results in the creation of lipid‐containing foam cells. Ang II increases the interleukin‐6 (IL‐6)‐mediated uptake of oxidized LDL by macrophages [50]. Moreover, Ang II upregulates lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) and 12‐lipoxygenase (12‐LO) and 15‐lipoxygenas (15‐LO) expression in human VSMC. Thus, these two actions are accelerating LDL oxidation within the cell and enabling the internalization of exogenous ox‐LDL, which could increase the susceptibility of human VSMC to transformation into foam cells [51].

The exposure of vascular cells to excess lipid (modified LDLs) with concomitant endothelial dysfunction/activation and the internalization and lipid deposits in the intima of vessel wall leads to further progression of atherosclerotic plaques [52]. Since advanced lesions predominantly consist of inflammatory cells, it is considered that at this stage progression of atherosclerosis is inflammation‐driven. Modified LDLs enhance a broad range inflammatory responses, including activation, recruitment and infiltration of different immune cells (monocytes, neutrophils, natural killer cells, mast cells and dendritic cells) although the contribution of circulating monocytes is the most important [52]. When monocytes infiltrate and reach the sub‐endothelium they differentiate into macrophages, under the stimulation of macrophage colony‐stimulating factor (M‐CSF). Macrophages are very adaptable cells that can undertake different phenotypes and functional characteristics, depending on the local microenvironment, which is a process known as ‘polarization’ [53, 54]. Distinct macrophage subtypes (M1 and M2) have been detected depending on the stage of atherosclerosis. Once differentiated, macrophages express high levels of pattern recognition receptors on their surface. These receptors have the ability to take up modified LDLs. Macrophages, then become lipid‐laden and convert into foam cells. There is a potential role that Ang II provoking recruitment and activation of both macrophages and T cells into the vessel wall, by stimulating the expression of pro‐inflammatory chemokines and cytokines, since both macrophages [55] and T cells express the AT1R on their surface [56, 57]. Ang II also increases monocyte chemoattractant protein‐1 (MCP‐1) expression in culture VSMCs as well as monocytes [58].

Importantly, Ang II induces the activation of several pro‐inflammatory transcription factors. One of them is nuclear factor kappa B (NF‐κB). Ang II activates NF‐κB via AT1R in vascular cells and mononuclear cells, both in vivo and in vitro [59, 60]. The increase Ang II activates NF‐κB by phosphorylating IκBα and p65 [61], which induces enhanced matrix metalloproteinase 9 (MMP‐9) expression [62]. The AT1R mediates most of the actions of Ang II, but experimental data suggest that AT2R is also involved in Ang II‐mediated NF‐κB activation in inflammatory cell recruitment [63]. Recently, both an increase in AT1R and ACE levels and activation of NF‐κB in heart have been reported in rat a model of a metabolic syndrome known as an inflammatory condition associated with accelerated atherogenesis [62, 64].

On the other hand, Ang II‐induced activation of NF‐kB could downregulate peroxisome proliferator‐activated receptors (PPARs), PPAR‐alpha and ‐gamma. This may diminish the anti‐inflammatory effect of PPARs, thus contributing to enhanced vascular inflammation, leading to the acceleration of atherosclerosis in mice deficient for apolipoprotein E(ApoE ‐/‐) mice [65]. Also, Ang II is inducing inflammation and remodelling of the vessel wall via activation of transcriptional mediator, Ets‐1, member of ETS family of transcription factors [66]. Recently, inflammatory actions of Ang II were diminished by sirtuin‐1 (SIRT‐1) activator SRT1720. Treatment with SRT1720 decreased expression of TNF‐a, IL‐6, MCP‐1, VCAM‐1, ICAM‐1, activation of NF‐kB, STAT3 and infiltration of inflammatory cells in atherosclerotic plaques, induced by Ang II [67]. In order to inhibit Ang II signaling, SIRT‐1 activation is a promising atheroprotective mechanism.

2.1.2. Role of RAS in atherosclerosis progression and acute complications

Over time continued plaque growth causes thickening and stiffening of the vessel wall and destabilizes it. This process results in a plaque rupture, which manifests as an occurrence of acute complications and development of ischaemic syndromes. Furthermore, the release of growth factors and cytokines by foam cells stimulates VSMC migration from the media into the intima. Upon arrival, these cells divide and produce extracellular matrix (ECM) components that contribute to the formation of the fibrous cap covering the plaque lipid core [68]. Also, Ang II triggers VSMCs to proliferate and migrate to the outer layer of the atherosclerotic plaques, where they produce growth factors and extracellular matrix proteins [69, 70]. The deposition of ECM components secreted by VSMCs in the plaques increases their size and eventually become occlusive. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors from blood leads to platelet activation, aggregation and the subsequent formation of a thrombus, which may compromise the arterial lumen [52]. The thrombogenicity of the plaque is favored by a disturbance in the balance of coagulation and fibrinolysis. The role of Ang II, as a mediator of thrombogenesis has been also supported by animal studies [71, 72]. Namely, models of elevated Ang II levels, elicited both genetically and via chronic Ang II infusion, have demonstrated increased tissue factor (TF) expression and increased plasma plasminogen activator inhibitor‐1 (PAI‐1) level [7375]. In vitro studies confirmed that Ang II induces the expression of TF in rat aortic endothelial cells [76] and human monocytes [77]. Chronic Ang II infusion induces platelet‐endothelial cell adhesion [78] and accelerates thrombus formation in both large arteries [71, 79] and arterioles [74]. TF in atherosclerotic plaques initiates blood coagulation, directly stimulates SMC proliferation and activates MMPs capable of degrading collagen. MMPs digest ECM scaffold, including the overlying fibrous cap, increasing plaque susceptibility to rupture. Moreover, Ang II induces release of MMP‐2 in murine VSMCs via p47phox cytosolic subunit of the NAD(P)H‐oxidase. Therefore, the activation of RAS contributes atherosclerotic plaque remodelling and potential destabilization via a NAD(P)H‐oxidase‐dependent activation of MMP‐2 [80]. Laxton et al. demonstrated in vitro that MMP‐8 cleaves Ang I to generate Ang II, and that MMP8‐knockout mice have a substantial reduction in formation of atherosclerotic lesions [81]. Moreover, an association between MMP8 gene variation and extent of coronary and carotid atherosclerosis [81, 82] was observed. Significant upregulation of MMP‐8 gene expression in carotid plaque tissue was observed in patients carrying haplotype G(‐381)T(‐799) of two MMP‐8 promoter polymorphisms rs11225395 (‐799 C/T) and rs1320632 (‐381 A/G) [82]. Recently, it was shown that Ang II treatment in vitro causes increased collagen I synthesis and galectin‐3 (Gal‐3) expression in mouse HL‐1 cardiomyocytes via protein kinase Calpha (PKC‐α) pathway [83]. Gal‐3 is involved in all processes active in atherosclerosis: cell adhesion, cell activation and chemoattraction, cell growth and differentiation [84]. An increase expression of Gal‐3 mRNA in human carotid atherosclerotic plaque tissue may be affected by rare genetic variants of the haplotype block, previously associated with Gal‐3 circulating levels [85, 86]. Diverse cellular processes in atherosclerosis are affected by microRNAs (miRs) and their expression are often tissue and disease‐specific [87, 88]. Recently, the prediction algorithms and computational methods were applied to identify novel miRs important in pathogenesis of early and advanced atherosclerosis [89]. Amongst a number of miRs upregulated in atherosclerotic plaque, miR‐155 shows dual properties in atherosclerosis and has particular interactions with RAS. Its activity could suppress Ang II‐induced extracellular signal‐regulated kinase (ERK1/2) phosphorylation and activation and regulate AT1R expression in different vascular cells [90, 91]. Moreover, it is shown that miR‐155 downregulates AT1R expression, but not other RAS components [90].

2.2. Main RAS molecules in atherosclerosis through the magnifying glass

It is evident that Ang II, as a main mediator of RAS, promotes the formation of atherosclerotic lesions. In animal models of disease, AT1R deficiency in ApoE ‐/‐ and LDL receptor (LDLR‐/‐) atherosclerotic mice attenuates progression of atherosclerotic lesions, suggesting that AT1R mediates most of the Ang II functions [92, 93]. Hyperlipidaemia upregulates AT1R whose activation augments vascular oxidative stress and accelerates atherosclerosis [93], particularly as oxidized lipid becomes a neo‐antigen that attracts components of the adaptive immune system to the vascular wall [94]. Consistent with this, AT1R deficiency causes a marked decrease in atherosclerotic lesion size in both the aortic root and arch of female and male mice, without a discernible effect on the composition. Also, aortic ATR2 mRNA expression is not altered in AT1R deficient mice, and AT2R deficiency is not affecting the lesion area or cellular composition [93].

Pharmacological inhibition of endothelial dysfunction and diet‐induced atherosclerosis in ApoE AT1R‐deficient mice dramatically attenuates the severity of atherosclerotic lesions [92, 95]. It is believed that the protective effects of the AT1R blockade with its antagonists (ARBs) include reduction of oxidative stress, reduction of inflammation and improvement in endothelial function [92]. Pharmacological blockade of AT1R reduces lipid accumulation and increases the level of collagen within the atheroma and thereby stabilizes the formation of atherosclerotic plaques in ApoE‐deficient mice [96] and in those with disrupted AT1R gene in bone marrow cells (BM) [97]. BM chimeric mice with disrupted BM AT1R show a reduced number of atherosclerotic lesions in the aorta and more stable plaques with reduced accumulation of BM‐derived cells compared to AT1R‐positive BM chimeric mice [97]. BM transplantation (BMT) from the ApoE‐/‐AT1R+/+ animals to the ApoE‐/‐AT1R‐/‐ mice could restore Ang II‐induced aggravation of atherosclerosis and plaque destabilization, even when the recipient's vascular cells do not express AT1R [98]. The contribution of AT1R in BM cells to the pathogenesis of atherosclerosis was demonstrated in LDL‐receptor‐deficient mice [99]. Hypertensive hypercholesterolemic ApoE‐/‐ mice with either normal or endogenously increased Ang II production (renovascular hypertension models) were generated in order to study the contribution of Ang II to plaque vulnerability [100]. Staging and morphology of plaques significantly differed among these groups of mice and revealed an accelerated atherosclerosis in hypertensive animals. Plaques from mice with high Ang II appeared to be vulnerable, whereas plaques from mice with unchanged Ang II levels and similar blood pressure values were stable [100]. This mouse model of vulnerable plaque induced in a mouse is important and mimics a pathophysiological state commonly found in humans.

The expression of ERK1/2 and pro‐inflammatory cytokines was reduced in supernatants of human carotid atheroma explant cultures treated with ARBs [101]. Also, in the same type of atheroma ATR1 blockade led to significantly reduced Ang II, MMP‐1, MMP‐8 expression and soluble elastin fragments [102]. This data recognized the ability of ATR1 blockade to modify plaque stability.

There are several beneficial effects assigned to the role of AT2R in atherosclerosis. AT2R overexpression in LDLR‐knockout mice reduces atherogenesis in the aorta, as well as, expression and activity of MMP‐2, MMP‐9 and collagen accumulation in atherosclerotic regions [103]. In the same model, the presence of AT2R modulated oxidative stress, by decreasing expression of LOX‐1, endothelial NO synthase (eNOS) and heme oxygenase‐1 (HO‐1) [104]. Also, in mice deficient for ApoE and AT2R on a diet rich in cholesterol, the atherosclerotic changes were exaggerated [105] which was shown as increased cellularity of atherosclerotic lesions [106]. After 16 weeks on a diet high in cholesterol, ApoE (‐/‐)/AT2R+ mice had significantly decreased a number of macrophages, VSMCs, lipids and collagen in the plaques due to apoptosis, compared to those deficient in AT2R gene [106]. Stimulation of AT2R by exogenous Ang II reduced atherogenesis in ApoE‐/‐/AT1R‐/‐ double knockout mice [107]. It is evident that AT2R exerts atheroprotective effects when AT1R is inhibited. Vascular AT2R stimulation in transgenic ApoE‐/‐ mice (AT2R‐Tg/ApoE‐/‐) significantly reduces atherosclerotic lesion development in an endothelial kinin/nitric oxide(NO)‐dependent manner and its anti‐oxidative effect is likely to be mediated by inhibition of the superoxide‐producing mononuclear leukocytes accumulation [108]. In ApoE‐deficient mice, direct stimulation of AT2R by agonist CGP42112 improves endothelial function and stabilizes atherosclerotic plaques [109].

Evidence suggests that AT2R and ACE2, as a part of the ACE2–Ang‐(1–7)–Mas axis, play a protective role in atherogenesis. Both factors have been detected within rabbit atherosclerotic plaques, AT2R and ACE2 immunoreactivity were observed in macrophages and alpha SMC actin‐positive cells [110]. ACE2 has been identified as a critical negative modulator of Ang II, counterbalancing the effects of ACE, by degrading Ang II and generating anti‐atherosclerotic Ang‐(1‐7). Genetic ACE2 deficiency underlines vascular inflammation and atherosclerosis in the ApoE‐/‐ mice [111]. Protective role of ACE2 and AT2R in cardiovascular pathology is supported by their decreased expression in male rat hearts on fructose‐rich diet [112].

Also, ACE2 deficiency either in a whole body or in bone marrow‐derived cells reduced atherosclerosis in LDLR‐/‐ mice through regulation of Ang II/Ang‐(1–7) peptides [113]. Overexpression of ACE2 in aortas of ApoE‐/‐ mice transfected with AdACE2 (recombinant ACE2 adenovirus encoding full‐length human ACE2 and co‐expressing the GFP protein) led to less prominent macrophage infiltration than in aortas from control mice [114]. Also, overexpression of ACE2 enhanced plaque stability in a rabbit model of atherosclerosis [115]. Abdominal aorta segments transfected with AdACE2 showed a delayed onset of atherosclerotic lesions with fewer macrophages, less lipid deposition, more collagen contents, decreased expression of Ang II, MCP‐1, LOX‐1 and increased angiotensin (1–7) levels in plaque tissue [116]. In two different models of vascular disease, both hyperlipidaemia‐induced atherosclerosis in ApoE‐/‐ mice and mechanical injury‐induced arterial neointimal hyperplasia in C57Bl6 mice, ACE2 deficiency resulted in significantly larger vascular lesions and neointimal hyperplasia compared with ACE2(+) controls [117]. ACE2 and exogenous Ang‐(1‐7) significantly inhibit early atherosclerotic lesion formation by preserving endothelial function and inhibiting of an inflammatory response in ApoE‐/‐ mice [118, 119]. ACE2 activity and protein production were increased in atherosclerotic plaques treated with losartan in vivo in and in vitro in VSMCs [120]. Candesartan treatment restores vasoprotective and atheroprotective effects of the ACE2/Ang (1‐7)/Mas receptor axis in high‐cholesterol diet‐fed ApoE‐/‐ mice due to the inhibition of the pro‐inflammatory‐redox AT1R‐mediated mechanism [121]. Increased ACE2 activation is considered to be a protective and compensatory mechanism that counterbalances ACE activity, and may play an important role in the treatment of atherosclerosis. Activation of ACE2/Ang (1‐7)/Mas receptor axis by ACE2 activator (XNT) attenuates thrombus formation and reduces platelet attachment to vessels [122]. ACE2 overexpression in THP‐1 (human acute monocytic leukemia cell line) in vitro decreases Ang II‐induced MCP‐1 production and this reduction is likely to be mediated by increased Ang (1‐7) levels [123]. Blockage of endogenously activated Ang‐(1‐7) by chronic infusion of A779 attenuated late atherosclerotic plaque stability in high fat diet fed ApoE‐/‐ mice [118]. All together ACE2 and Ang‐(1–7) could be a therapeutic target for attenuation of atherosclerosis and the treatment of cardiovascular diseases.

3. Genetics of RAS in atherosclerosis

Over the past two decades, a large number of genetic investigations have been carried out to examine the association between genetic variants of RAS genes and vascular diseases, such as myocardial infarction, coronary artery disease and stroke. RAS genes were thoroughly associated with different risk factors for atherosclerosis, among which hypertension has a central role bearing in mind primary physiological role of RAS. Different cardiovascular phenotypes, such as left ventricular hypertrophy, artery stenosis, artery stiffness and vascular remodelling were studied as well.

The story started with unforgettable discovery of ACE insertion/deletion (I/D) polymorphism (rs4340) associated with increased levels of ACE [124, 125]. This was the first discovery that implicated what is now fully accepted, that naturally occurring variations in DNA sequences, or polymorphisms (SNPs, insertion/deletions, copy number variations), mostly have the modifying effect in the development of atherosclerosis and together with gene‐gene and gene‐environment interactions are making an important contribution to the risk.

The most widely studied polymorphism in the RAS is I/D polymorphism, a287‐bp Alu repeat element in intron 16 of ACE gene. It has been considered as a functional variant, since the ACE DD genotype was associated with higher circulating [124126] and tissue mRNA levels of ACE [127, 128]. Among 78 variations that were found by ACE gene sequencing, 17 were in absolute linkage disequilibrium with the I/D polymorphism [129]. First genetic association studies were focused on ACE D allele effect on blood pressure [130, 131] and hypertension [132134].

In atherosclerosis, most of the studies so far have been investigating ACE I/D polymorphism in association with subclinical and intermediate atherosclerotic phenotypes, such as intima‐media thickness (IMT) with conflicting results. Meta‐analysis of these studies uncovered moderate positive association of ACE D allele with common carotid IMT [135]. The association of ACE I/D polymorphism studies with advanced atherosclerosis has still been rare. As different mechanisms might be dominating the different stage of atherosclerosis development, as described previously in this chapter, it is always of importance to perform a genetic association study on early non‐stenotic atherosclerosis and advanced stenotic atherosclerosis. A significant independent effect of DD genotype on plaque presence in patients with high‐grade carotid stenosis (>70%) was noticed only in normotensive patients [136]. Another study failed to support the hypothesis that ACE genotype is a predictor of either the prevalence or the extent of atherosclerotic plaques but only in young adults [137].

Nevertheless, its role in atherosclerotic complications was noticed in a large‐scale meta‐analysis where the significant associations with ischemic stroke in approximately 18,000 cases and 58,000 controls were identified for four gene polymorphisms among which was ACE I/D [138]. An astonishing discovery was made recently, 23 years after Tiret et al. [124] found that ACE I/D influence on serum ACE levels. It was observed ACE expression appears to be regulated by mitochondrial uncoupling proteins (UCPs). Serum ACE activity was influenced by allele variants in UCP2 and UCP3 genes. This was the first evidence of association of serum ACE with a genetic variant outside the ACE gene [139]. This gave a new perspective on ACE investigation, suggesting that cellular feedback regulation might exist between ACE and UCPs. Even so, genetic variations in UCPs and SIRTs were recently associated with the atherosclerotic plaque existence [140] and morphology [141].

Also, both Ang II receptor genes, AT1R and AT2R, have many SNPs in the coding and its flanking regions, but the most studied are AT1R A1166C and AT2R ‐1332 A/G (+G1675A).

The A1166C polymorphism (rs5186) is located in the 3′ untranslated region (UTR) of AT1R gene. Primarily, it was investigated in association with hypertension but with inconsistent findings. Association with hypertension was established in a certain subgroups of patients, e.g. only in subjects with severe, early onset, form of disease [142] and in long‐term‐treated subjects and/or with a family history of hypertension (HT) [143, 144] or in subjects with hypercholesterolaemia [145] or in males only [146]. A systematic review and a meta‐analysis of the rs5186 variant failed to present sufficient evidence that polymorphisms in the AT1R gene are risk factors for hypertension [147].

Besides hypertension, rs5186 was associated with increased reactivity to Ang II in human arteries [148] and blood pressure response to exogenous Ang II [149]. In the context of atherosclerosis and different atherosclerotic phenotypes, previous studies addressed this polymorphism with inconsistent data. Some failed to show any significant effect for the A1166C polymorphism on mean IMT, carotid plaque formation [150] or internal carotid artery (ICA) stenosis [151]. The C‐allele has been associated with a thicker carotid IMT in women [152] and increased IMT and IMT/D (common carotid artery diameter) ratio in hypertensive subjects [153]. A meta‐analysis performed in 2011 suggests that the AT1R gene A1166C polymorphism is not associated with susceptibility to ischemic stroke [154]. However, the association between the AT1R 1166C allele and the presence of hypoechoic carotid plaques was recently found [155]. Confronting results could be attributed to differences in age, gender, belonging to different populations or ethnic groups, or different non‐genomic and other external factors. The AT1R A1166C polymorphism is positioned in the target site for miR‐155 [156, 157]. It was shown experimentally that human miR‐155 downregulates expression of the 1166A allele alone [156], and that interaction between authentic miR‐155 and the C allele is diminished, in a way that its ability to regulate AT1R gene expression is altered [157].

The AT2R, ‐1332 A/G polymorphism (rs1403543) located within the intron 1 of the gene was proposed to be functional, by affecting the mRNA alternative splicing and gene expression of AT2R. However, novel findings suggest that ‐1332 A/G might modulate protein expression, but not mRNA splicing [158, 159]. There are few studies that have been investigating this polymorphism in association with the presence of atherosclerotic plaques. Our study performed recently suggests that AT2R ‐1332 A/G polymorphism is a reliable gender‐specific risk factor for carotid atherosclerotic plaque presence in females and could modify the inter‐individual risk of cerebrovascular insult (CVI) among males with advanced carotid atherosclerosis [160]. It is still not clear which of the alleles, A or G, are more likely to carry a significant risk, even for hypertension and different cardiovascular phenotypes that were reproducibly investigated [161]. It was shown that a ‐1332 A/G polymorphism represents a risk factor for cardiovascular diseases and severe atherosclerosis by modifying systemic inflammation, especially in hypertensive males [162]. It is known that AT2R is expressed at low levels in the healthy adult vasculature. AT2R effects on cardiovascular structure and function may only become detectable under pathological conditions and/or after AT1R blockade. Expression of AT2R in human carotid atherosclerotic plaques was previously detected [163]. However, whether the stimulation of the AT2R is protective or deleterious in human atherosclerosis remains unresolved. The impact of AT2R during atherosclerosis or tissue injury should be studied by direct stimulation of AT2R to address potential therapeutic potential [164, 165].

4. Conclusion

Activation of RAS in the vascular wall has modulatory activities in the development of atherosclerosis by stimulating a series of cellular and molecular events. The balance between activation and repression of RAS could be decisive in the pathological remodelling, endothelial dysfunction and pathogenesis of atherosclerosis. Unfavorable and favorable effects of RAS molecules and their genetic variations, as well as consequently induced pathways, affect atherosclerosis development and following clinical events. This could have potential towards clinical application for risk stratification and therapeutics.


This work was supported by the Grants of the Ministry of Education, Science and Technological Development, Republic of Serbia: III41028 and OI 175085.


1 - Oudit GY, Crackower MA, Backx PH, Penninger JM. The role of ACE2 in cardiovascular physiology. Trends in Cardiovascular Medicine. 2003;13:93–101.
2 - Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin‐converting enzyme. Cloning and functional expression as a captopril‐insensitive carboxypeptidase. The Journal of Biological Chemistry. 2000;275:33238–43.
3 - Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin‐converting enzyme‐related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circulation Research. 2000;87:E1–9.
4 - Santos RA, Ferreira AJ. Angiotensin‐(1–7) and the renin‐angiotensin system. Current Opinion in Nephrology and Hypertension. 2007;16:122–8.
5 - Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin‐(1‐7) is an endogenous ligand for the G protein‐coupled receptor Mas. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:8258–63.
6 - Nagata S, Kato J, Sasaki K, Minamino N, Eto T, Kitamura K. Isolation and identification of proangiotensin‐12, a possible component of the renin‐angiotensin system. Biochemical and Biophysical Research Communications. 2006;350:1026–31.
7 - Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, et al. Mass‐spectrometric identification of a novel angiotensin peptide in human plasma. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:297–302.
8 - Coutinho DC, Foureaux G, Rodrigues KD, Salles RL, Moraes PL, Murca TM, et al. Cardiovascular effects of angiotensin A: a novel peptide of the renin‐angiotensin system. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2014;15:480–6.
9 - Lautner RQ, Villela DC, Fraga‐Silva RA, Silva N, Verano‐Braga T, Costa‐Fraga F, et al. Discovery and characterization of alamandine: a novel component of the renin‐angiotensin system. Circulation Research. 2013;112:1104–11.
10 - Etelvino GM, Peluso AA, Santos RA. New components of the renin‐angiotensin system: alamandine and the MAS‐related G protein‐coupled receptor D. Current Hypertension Reports. 2014;16:433.
11 - Bader M, Ganten D. Update on tissue renin‐angiotensin systems. Journal of Molecular Medicine (Berlin, Germany). 2008;86:615–21.
12 - Campbell DJ. Clinical relevance of local Renin Angiotensin systems. Frontiers in Endocrinology. 2014;5:113.
13 - Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin‐angiotensin systems. Physiological Reviews. 2006;86:747–803.
14 - Speth RC, Giese MJ. Update on the Renin-Angiotensin System. J Pharmacol Clin Toxicol. 2013;1:1004.
15 - Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. The Journal of Clinical Investigation. 2002;109:1417–27.
16 - Nguyen G, Muller DN. The biology of the (pro)renin receptor. Journal of the American Society of Nephrology: JASN. 2010;21:18–23.
17 - Ahmad S, Simmons T, Varagic J, Moniwa N, Chappell MC, Ferrario CM. Chymase‐dependent generation of angiotensin II from angiotensin‐(1–12) in human atrial tissue. PloS One. 2011;6:e28501.
18 - Ferrario CM, Varagic J, Habibi J, Nagata S, Kato J, Chappell MC, et al. Differential regulation of angiotensin‐(1–12) in plasma and cardiac tissue in response to bilateral nephrectomy. American Journal of Physiology Heart and Circulatory Physiology. 2009;296:H1184–92.
19 - Kumar R, Singh VP, Baker KM. The intracellular renin‐angiotensin system: a new paradigm. Trends in Endocrinology and Metabolism: TEM. 2007;18:208–14.
20 - Simoes e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin‐(1‐7) and Mas receptor axis in inflammation and fibrosis. British Journal of Pharmacology. 2013;169:477–92.
21 - Ferrario CM. New physiological concepts of the renin‐angiotensin system from the investigation of precursors and products of angiotensin I metabolism. Hypertension. 2010;55:445–52.
22 - van Kats JP, de Lannoy LM, Jan Danser AH, van Meegen JR, Verdouw PD, Schalekamp MA. Angiotensin II type 1 (AT1) receptor‐mediated accumulation of angiotensin II in tissues and its intracellular half‐life in vivo. Hypertension. 1997;30:42–9.
23 - Kurdi M, De Mello WC, Booz GW. Working outside the system: an update on the unconventional behavior of the renin‐angiotensin system components. The International Journal of Biochemistry & Cell Biology. 2005;37:1357–67.
24 - Vargas F, Rodriguez‐Gomez I, Vargas‐Tendero P, Jimenez E, Montiel M. The renin‐angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations. The Journal of Endocrinology. 2012;213:25–36.
25 - Kumar R, Boim MA. Diversity of pathways for intracellular angiotensin II synthesis. Current opinion in nephrology and hypertension. 2009;18:33–9.
26 - Fyhrquist F, Saijonmaa O. Renin‐angiotensin system revisited. Journal of Internal Medicine. 2008;264:224–36.
27 - Filipeanu CM, Henning RH, de Zeeuw D, Nelemans A. Intracellular Angiotensin II and cell growth of vascular smooth muscle cells. British Journal of Pharmacology. 2001;132:1590–6.
28 - De Mello WC. Intracellular angiotensin II as a regulator of muscle tone in vascular resistance vessels. Pathophysiological implications. Peptides. 2016;78:87–90.
29 - Sata M, Fukuda D. Crucial role of renin‐angiotensin system in the pathogenesis of atherosclerosis. The Journal of Medical Investigation: JMI. 2010;57:12–25.
30 - Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E‐deficient mice. The Journal of Clinical Investigation. 2000;105:1605–12.
31 - Touyz RM. Reactive oxygen species and angiotensin II signaling in vascular cells ‐‐ implications in cardiovascular disease. Brazilian Journal of Medical and Biological Research [Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica]. 2004;37:1263–73.
32 - Montezano AC, Touyz RM. Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research. Antioxidants & Redox Signaling. 2014;20:164–82.
33 - Min LJ, Mogi M, Iwai M, Horiuchi M. Signaling mechanisms of angiotensin II in regulating vascular senescence. Ageing Research Reviews. 2009;8:113–21.
34 - Nickenig G, Harrison DG. The AT(1)‐type angiotensin receptor in oxidative stress and atherogenesis: Part II: AT(1) receptor regulation. Circulation. 2002;105:530–6.
35 - Huang J, Hara Y, Anrather J, Speth RC, Iadecola C, Pickel VM. Angiotensin II subtype 1A (AT1A) receptors in the rat sensory vagal complex: subcellular localization and association with endogenous angiotensin. Neuroscience. 2003;122:21–36.
36 - Clausmeyer S, Reinecke A, Farrenkopf R, Unger T, Peters J. Tissue‐specific expression of a rat renin transcript lacking the coding sequence for the prefragment and its stimulation by myocardial infarction. Endocrinology. 2000;141:2963–70.
37 - Peters J, Clausmeyer S. Intracellular sorting of renin: cell type specific differences and their consequences. Journal of Molecular and Cellular Cardiology. 2002;34:1561–8.
38 - Peters J, Kranzlin B, Schaeffer S, Zimmer J, Resch S, Bachmann S, et al. Presence of renin within intramitochondrial dense bodies of the rat adrenal cortex. The American Journal of Physiology. 1996;271:E439–50.
39 - Shatanawi A, Romero MJ, Iddings JA, Chandra S, Umapathy NS, Verin AD, et al. Angiotensin II‐induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen‐activated protein kinase/arginase pathway. American Journal of Physiology Cell Physiology. 2011;300:C1181–92.
40 - Seto SW, Krishna SM, Yu H, Liu D, Khosla S, Golledge J. Impaired acetylcholine‐induced endothelium‐dependent aortic relaxation by caveolin‐1 in angiotensin II‐infused apolipoprotein‐E (ApoE‐/‐) knockout mice. PloS One. 2013;8:e58481.
41 - Gomolak JR, Didion SP. Angiotensin II‐induced endothelial dysfunction is temporally linked with increases in interleukin‐6 and vascular macrophage accumulation. Frontiers in Physiology. 2014;5:396.
42 - Weiss D, Kools JJ, Taylor WR. Angiotensin II‐induced hypertension accelerates the development of atherosclerosis in apoE‐deficient mice. Circulation. 2001;103:448–54.
43 - Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule‐1 via nuclear factor‐kappaB activation induced by intracellular oxidative stress. Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:645–51.
44 - Pastore L, Tessitore A, Martinotti S, Toniato E, Alesse E, Bravi MC, et al. Angiotensin II stimulates intercellular adhesion molecule‐1 (ICAM‐1) expression by human vascular endothelial cells and increases soluble ICAM‐1 release in vivo. Circulation. 1999;100:1646–52.
45 - Suzuki Y, Ruiz‐Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. The International Journal of Biochemistry & Cell Biology. 2003;35:881–900.
46 - Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular inflammation. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2005;11:Ra194–205.
47 - Touyz RM. Molecular and cellular mechanisms in vascular injury in hypertension: role of angiotensin II. Current Opinion in Nephrology and Hypertension. 2005;14:125–31.
48 - Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM. Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circulation research. 1997;81:970–6.
49 - Song H, Gao D, Chen L, Seta K, McLaughlin JS, Wei C. Angiotensin II‐mediated apoptosis on human vascular smooth muscle cells. Journal of Cardiothoracic‐Renal Research. 2006;1:135–9.
50 - Keidar S, Heinrich R, Kaplan M, Hayek T, Aviram M. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin‐6. Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1464–9.
51 - Limor R, Kaplan M, Sawamura T, Sharon O, Keidar S, Weisinger G, et al. Angiotensin II increases the expression of lectin‐like oxidized low‐density lipoprotein receptor‐1 in human vascular smooth muscle cells via a lipoxygenase‐dependent pathway. American Journal of Hypertension. 2005;18:299–307.
52 - Badimon L, Vilahur G. Thrombosis formation on atherosclerotic lesions and plaque rupture. Journal of internal medicine. 2014;276:618–32.
53 - Libby P, Nahrendorf M, Swirski FK. Monocyte heterogeneity in cardiovascular disease. Seminars in Immunopathology. 2013;35:553–62.
54 - Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN. Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. International Journal of Cardiology. 2015;184:436–45.
55 - Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Takiuchi S, Moriguchi K, et al. Upregulation of renin‐angiotensin system during differentiation of monocytes to macrophages. Journal of Hypertension. 1999;17:537–45.
56 - Jurewicz M, McDermott DH, Sechler JM, Tinckam K, Takakura A, Carpenter CB, et al. Human T and natural killer cells possess a functional renin‐angiotensin system: further mechanisms of angiotensin II‐induced inflammation. Journal of the American Society of Nephrology: JASN. 2007;18:1093–102.
57 - Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, et al. Regulation of T‐cell function by endogenously produced angiotensin II. American Journal of Physiology Regulatory, Integrative and Comparative Physiology. 2009;296:R208–16.
58 - Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein‐1 gene expression in rat vascular smooth muscle cells. Circulation Research. 1998;83:952–9.
59 - Hernandez‐Presa M, Bustos C, Ortego M, Tunon J, Renedo G, Ruiz‐Ortega M, et al. Angiotensin‐converting enzyme inhibition prevents arterial nuclear factor‐kappa B activation, monocyte chemoattractant protein‐1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation. 1997;95:1532–41.
60 - Kranzhofer R, Browatzki M, Schmidt J, Kubler W. Angiotensin II activates the proinflammatory transcription factor nuclear factor‐kappaB in human monocytes. Biochemical and Biophysical Research Communications. 1999;257:826–8.
61 - Kim JM, Heo HS, Ha YM, Ye BH, Lee EK, Choi YJ, et al. Mechanism of Ang II involvement in activation of NF‐kappaB through phosphorylation of p65 during aging. Age (Dordrecht, Netherlands). 2012;34:11–25.
62 - Bundalo M, Zivkovic M, Culafic T, Stojiljkovic M, Koricanac G, Stankovic A. Oestradiol Treatment counteracts the effect of fructose‐rich diet on matrix metalloproteinase 9 expression and NFkappaB activation. Folia Biologica. 2015;61:233–40.
63 - Esteban V, Lorenzo O, Ruperez M, Suzuki Y, Mezzano S, Blanco J, et al. Angiotensin II, via AT1 and AT2 receptors and NF‐kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. Journal of the American Society of Nephrology: JASN. 2004;15:1514–29.
64 - Bundalo M, Zivkovic M, Tepavcevic S, Culafic T, Koricanac G, Stankovic A. Fructose‐rich diet‐induced changes in the expression of the renin angiotensin system molecules in the heart of ovariectomized female rats could be reversed by estradiol. Hormone and Metabolic Research = Hormon‐ und Stoffwechselforschung = Hormones et Metabolisme. 2015;47:521–7.
65 - Tham DM, Martin‐McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, et al. Angiotensin II is associated with activation of NF‐kappaB‐mediated genes and downregulation of PPARs. Physiological Genomics. 2002;11:21–30.
66 - Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, et al. Ets‐1 is a critical regulator of Ang II‐mediated vascular inflammation and remodeling. The Journal of Clinical Investigation. 2005;115:2508–16.
67 - Chen YX, Zhang M, Cai Y, Zhao Q, Dai W. The Sirt1 activator SRT1720 attenuates angiotensin II‐induced atherosclerosis in apoE(‐)/(‐) mice through inhibiting vascular inflammatory response. Biochemical and Biophysical Research Communications. 2015;465:732–8.
68 - Koga J, Aikawa M. Crosstalk between macrophages and smooth muscle cells in atherosclerotic vascular diseases. Vascular Pharmacology. 2012;57:24–8.
69 - Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacological Reviews. 2000;52:639–72.
70 - Zhang F, Hu Y, Xu Q, Ye S. Different effects of angiotensin II and angiotensin‐(1‐7) on vascular smooth muscle cell proliferation and migration. PloS One. 2010;5:e12323.
71 - Kaminska M, Mogielnicki A, Stankiewicz A, Kramkowski K, Domaniewski T, Buczko W, et al. Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats. Journal of Physiology and Pharmacology: an Official Journal of the Polish Physiological Society. 2005;56:571–85.
72 - Ishikawa M, Sekizuka E, Yamaguchi N, Nakadate H, Terao S, Granger DN, et al. Angiotensin II type 1 receptor signaling contributes to platelet‐leukocyte‐endothelial cell interactions in the cerebral microvasculature. American journal of Physiology Heart and Circulatory Physiology. 2007;292:H2306–15.
73 - Doller A, Gauer S, Sobkowiak E, Geiger H, Pfeilschifter J, Eberhardt W. Angiotensin II induces renal plasminogen activator inhibitor‐1 and cyclooxygenase‐2 expression post‐transcriptionally via activation of the mRNA‐stabilizing factor human‐antigen R. The American Journal of Pathology. 2009;174:1252–63.
74 - Senchenkova EY, Russell J, Almeida‐Paula LD, Harding JW, Granger DN. Angiotensin II‐mediated microvascular thrombosis. Hypertension. 2010;56:1089–95.
75 - Nakamura S, Nakamura I, Ma L, Vaughan DE, Fogo AB. Plasminogen activator inhibitor‐1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney International. 2000;58:251–9.
76 - Nishimura H, Tsuji H, Masuda H, Nakagawa K, Nakahara Y, Kitamura H, et al. Angiotensin II increases plasminogen activator inhibitor‐1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thrombosis and Haemostasis. 1997;77:1189–95.
77 - He M, He X, Xie Q, Chen F, He S. Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes. Thrombosis Research. 2006;117:579–90.
78 - Vital SA, Terao S, Nagai M, Granger DN. Mechanisms underlying the cerebral microvascular responses to angiotensin II‐induced hypertension. Microcirculation (New York, NY: 1994). 2010;17:641–9.
79 - Mogielnicki A, Chabielska E, Pawlak R, Szemraj J, Buczko W. Angiotensin II enhances thrombosis development in renovascular hypertensive rats. Thrombosis and Haemostasis. 2005;93:1069–76.
80 - Luchtefeld M, Grote K, Grothusen C, Bley S, Bandlow N, Selle T, et al. Angiotensin II induces MMP‐2 in a p47phox‐dependent manner. Biochemical and Biophysical Research Communications. 2005;328:183–8.
81 - Laxton RC, Hu Y, Duchene J, Zhang F, Zhang Z, Leung KY, et al. A role of matrix metalloproteinase‐8 in atherosclerosis. Circulation Research. 2009;105:921–9.
82 - Djuric T, Stankovic A, Koncar I, Radak D, Davidovic L, Alavantic D, et al. Association of MMP‐8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study. Atherosclerosis. 2011;219:673–8.
83 - Song X, Qian X, Shen M, Jiang R, Wagner MB, Ding G, et al. Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin‐3 expression. Biochimica et Biophysica Acta. 2015;1853:513–21.
84 - Dumic J, Dabelic S, Flogel M. Galectin‐3: an open‐ended story. Biochimica et Biophysica Acta. 2006;1760:616–35.
85 - Djordjevic A, Zivkovic M, Stankovic A, Zivotic I, Koncar I, Davidovic L, et al. Genetic Variants in the Vicinity of LGALS-3 Gene and LGALS-3 mRNA Expression in Advanced Carotid Atherosclerosis: An Exploratory Study. Journal of clinical laboratory analysis. 2016;30:1150–7.
86 - de Boer RA, Verweij N, van Veldhuisen DJ, Westra HJ, Bakker SJ, Gansevoort RT, et al. A genome‐wide association study of circulating galectin‐3. PloS One. 2012;7:e47385.
87 - Raitoharju E, Lyytikainen LP, Levula M, Oksala N, Mennander A, Tarkka M, et al. miR‐21, miR‐210, miR‐34a, and miR‐146a/b are up‐regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011;219:211–7.
88 - Levula M, Oksala N, Airla N, Zeitlin R, Salenius JP, Jarvinen O, et al. Genes involved in systemic and arterial bed dependent atherosclerosis‐‐Tampere Vascular study. PloS One. 2012;7:e33787.
89 - Jovanovic I, Zivkovic M, Jovanovic J, Djuric T, Stankovic A. The co‐inertia approach in identification of specific microRNA in early and advanced atherosclerosis plaque. Medical Hypotheses. 2014;83:11–5.
90 - Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, et al. Endothelial enriched microRNAs regulate angiotensin II‐induced endothelial inflammation and migration. Atherosclerosis. 2011;215:286–93.
91 - Cheng W, Liu T, Jiang F, Liu C, Zhao X, Gao Y, et al. microRNA‐155 regulates angiotensin II type 1 receptor expression in umbilical vein endothelial cells from severely pre‐eclamptic pregnant women. International Journal of Molecular Medicine. 2011;27:393–9.
92 - Wassmann S, Czech T, van Eickels M, Fleming I, Bohm M, Nickenig G. Inhibition of diet‐induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double‐knockout mice. Circulation. 2004;110:3062–7.
93 - Daugherty A, Rateri DL, Lu H, Inagami T, Cassis LA. Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor. Circulation. 2004;110:3849–57.
94 - Caligiuri G, Paulsson G, Nicoletti A, Maseri A, Hansson GK. Evidence for antigen‐driven T‐cell response in unstable angina. Circulation. 2000;102:1114–9.
95 - Li Z, Iwai M, Wu L, Liu HW, Chen R, Jinno T, et al. Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. Hypertension. 2004;44:758–63.
96 - Fukuda D, Enomoto S, Hirata Y, Nagai R, Sata M. The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2010;64:712–7.
97 - Fukuda D, Sata M, Ishizaka N, Nagai R. Critical role of bone marrow angiotensin II type 1 receptor in the pathogenesis of atherosclerosis in apolipoprotein E deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:90–6.
98 - Fukuda D, Sata M. Role of bone marrow renin‐angiotensin system in the pathogenesis of atherosclerosis. Pharmacology & Therapeutics. 2008;118:268–76.
99 - Cassis LA, Rateri DL, Lu H, Daugherty A. Bone marrow transplantation reveals that recipient AT1a receptors are required to initiate angiotensin II‐induced atherosclerosis and aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:380–6.
100 - Mazzolai L, Duchosal MA, Korber M, Bouzourene K, Aubert JF, Hao H, et al. Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE‐/‐ mice. Hypertension. 2004;44:277–82.
101 - Clancy P, Koblar SA, Golledge J. Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation. Atherosclerosis. 2014;236:108–15.
102 - Clancy P, Seto SW, Koblar SA, Golledge J. Role of the angiotensin converting enzyme 1/angiotensin II/angiotensin receptor 1 axis in interstitial collagenase expression in human carotid atheroma. Atherosclerosis. 2013;229:331–7.
103 - Dandapat A, Hu CP, Chen J, Liu Y, Khan JA, Remeo F, et al. Over‐expression of angiotensin II type 2 receptor (agtr2) decreases collagen accumulation in atherosclerotic plaque. Biochemical and Biophysical Research Communications. 2008;366:871–7.
104 - Hu C, Dandapat A, Chen J, Liu Y, Hermonat PL, Carey RM, et al. Over‐expression of angiotensin II type 2 receptor (agtr2) reduces atherogenesis and modulates LOX‐1, endothelial nitric oxide synthase and heme‐oxygenase‐1 expression. Atherosclerosis. 2008;199:288–94.
105 - Iwai M, Chen R, Li Z, Shiuchi T, Suzuki J, Ide A, et al. Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E‐null mice. Circulation. 2005;112:1636–43.
106 - Sales VL, Sukhova GK, Lopez‐Ilasaca MA, Libby P, Dzau VJ, Pratt RE. Angiotensin type 2 receptor is expressed in murine atherosclerotic lesions and modulates lesion evolution. Circulation. 2005;112:3328–36.
107 - Tiyerili V, Mueller CF, Becher UM, Czech T, van Eickels M, Daiber A, et al. Stimulation of the AT2 receptor reduced atherogenesis in ApoE(‐/‐)/AT1A(‐/‐) double knock out mice. Journal of Molecular and Cellular Cardiology. 2012;52:630–7.
108 - Takata H, Yamada H, Kawahito H, Kishida S, Irie D, Kato T, et al. Vascular angiotensin II type 2 receptor attenuates atherosclerosis via a kinin/NO‐dependent mechanism. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2015;16:311–20.
109 - Kljajic ST, Widdop RE, Vinh A, Welungoda I, Bosnyak S, Jones ES, et al. Direct AT(2) receptor stimulation is athero‐protective and stabilizes plaque in apolipoprotein E‐deficient mice. International Journal of Cardiology. 2013;169:281–7.
110 - Zulli A, Burrell LM, Widdop RE, Black MJ, Buxton BF, Hare DL. Immunolocalization of ACE2 and AT2 receptors in rabbit atherosclerotic plaques. The journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society. 2006;54:147–50.
111 - Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, et al. Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circulation Research. 2010;107:888–97.
112 - Bundalo MM, Zivkovic MD, Romic S, Tepavcevic SN, Koricanac GB, Djuric TM, et al. Fructose‐rich diet induces gender‐specific changes in expression of the renin‐angiotensin system in rat heart and upregulates the ACE/AT1R axis in the male rat aorta. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2016;17:1470320316642915.
113 - Thatcher SE, Zhang X, Howatt DA, Lu H, Gurley SB, Daugherty A, et al. Angiotensin‐converting enzyme 2 deficiency in whole body or bone marrow‐derived cells increases atherosclerosis in low‐density lipoprotein receptor‐/‐ mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:758–65.
114 - Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, et al. Angiotensin converting enzyme‐2 confers endothelial protection and attenuates atherosclerosis. American Journal of Physiology Heart and Circulatory Physiology. 2008;295:H1377–84.
115 - Dong B, Zhang C, Feng JB, Zhao YX, Li SY, Yang YP, et al. Overexpression of ACE2 enhances plaque stability in a rabbit model of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1270–6.
116 - Zhang C, Zhao YX, Zhang YH, Zhu L, Deng BP, Zhou ZL, et al. Angiotensin‐converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:15886–91.
117 - Sahara M, Ikutomi M, Morita T, Minami Y, Nakajima T, Hirata Y, et al. Deletion of angiotensin‐converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation. Cardiovascular Research. 2014;101:236–46.
118 - Yang J, Yang X, Meng X, Dong M, Guo T, Kong J, et al. Endogenous activated angiotensin‐(1‐7) plays a protective effect against atherosclerotic plaques unstability in high fat diet fed ApoE knockout mice. International Journal of Cardiology. 2015;184:645–52.
119 - Tesanovic S, Vinh A, Gaspari TA, Casley D, Widdop RE. Vasoprotective and atheroprotective effects of angiotensin (1‐7) in apolipoprotein E‐deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:1606–13.
120 - Zhang YH, Hao QQ, Wang XY, Chen X, Wang N, Zhu L, et al. ACE2 activity was increased in atherosclerotic plaque by losartan: possible relation to anti‐atherosclerosis. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2015;16:292–300.
121 - Pernomian L, do Prado AF, Gomes MS, Pernomian L, da Silva CH, Gerlach RF, et al. MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin‐converting enzyme 2‐angiotensin‐(1‐7)‐MAS axis functionality. European Journal of Pharmacology. 2015;764:173–88.
122 - Fraga‐Silva RA, Sorg BS, Wankhede M, Dedeugd C, Jun JY, Baker MB, et al. ACE2 activation promotes antithrombotic activity. Molecular Medicine (Cambridge, Mass). 2010;16:210–5.
123 - Guo YJ, Li WH, Wu R, Xie Q, Cui LQ. ACE2 overexpression inhibits angiotensin II‐induced monocyte chemoattractant protein‐1 expression in macrophages. Archives of Medical Research. 2008;39:149–54.
124 - Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I‐converting enzyme (ACE) gene controls plasma ACE levels. American Journal of Human Genetics. 1992;51:197–205.
125 - Rigat B, Hubert C, Alhenc‐Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I‐converting enzyme gene accounting for half the variance of serum enzyme levels. The Journal of Clinical Investigation. 1990;86:1343–6.
126 - Ay C, Bencur P, Vormittag R, Sailer T, Jungbauer C, Vukovich T, et al. The angiotensin‐converting enzyme insertion/deletion polymorphism and serum levels of angiotensin‐converting enzyme in venous thromboembolism. Data from a case control study. Thrombosis and Haemostasis. 2007;98:777–82.
127 - Mizuiri S, Hemmi H, Kumanomidou H, Iwamoto M, Miyagi M, Sakai K, et al. Angiotensin‐converting enzyme (ACE) I/D genotype and renal ACE gene expression. Kidney International. 2001;60:1124–30.
128 - Suehiro T, Morita T, Inoue M, Kumon Y, Ikeda Y, Hashimoto K. Increased amount of the angiotensin‐converting enzyme (ACE) mRNA originating from the ACE allele with deletion. Human Genetics. 2004;115:91–6.
129 - Rieder MJ, Taylor SL, Clark AG, Nickerson DA. Sequence variation in the human angiotensin converting enzyme. Nature Genetics. 1999;22:59–62.
130 - Schunkert H, Hense HW, Muscholl M, Luchner A, Riegger GA. Association of angiotensin converting enzyme activity and arterial blood pressure in a population‐based sample. Journal of Hypertension. 1996;14:571–5.
131 - Stankovic A, Ilic N, Zunic Z, Glisic S, Alavantic D. Association of the insertion/deletion polymorphism at the angiotensin I-converting enzyme locus with arterial blood pressure: population-based study. Yugoslav Medical Biochemistry. 1999;18:141–7.
132 - O’Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer EJ, et al. Evidence for association and genetic linkage of the angiotensin‐converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham heart study. Circulation. 1998;97:1766–72.
133 - Morris BJ, Zee RY, Schrader AP. Different frequencies of angiotensin‐converting enzyme genotypes in older hypertensive individuals. The Journal of Clinical Investigation. 1994;94:1085–9.
134 - Stankovic A, Zivkovic M, Alavantic D. Angiotensin I‐converting enzyme gene polymorphism in a Serbian population: a gender‐specific association with hypertension. Scandinavian Journal of Clinical and Laboratory Investigation. 2002;62:469–75.
135 - Sayed‐Tabatabaei FA, Houwing‐Duistermaat JJ, van Duijn CM, Witteman JC. Angiotensin‐converting enzyme gene polymorphism and carotid artery wall thickness: a meta‐analysis. Stroke; A Journal of Cerebral Circulation. 2003;34:1634–9.
136 - Kolakovic A, Zivkovic M, Radak D, Djuric T, Koncar I, Davidovic L, et al. The association of ACE I/D gene polymorphism with severe carotid atherosclerosis in patients undergoing carotid endarterectomy. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2012;13:141–7.
137 - Scheer WD, Boudreau DA, Hixson JE, McGill HC, Newman WP, 3rd, Tracy RE, et al. ACE insert/delete polymorphism and atherosclerosis. Atherosclerosis. 2005;178:241–7.
138 - Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta‐analysis of genetic studies in ischemic stroke: thirty‐two genes involving approximately 18,000 cases and 58,000 controls. Archives of Neurology. 2004;61:1652–61.
139 - Dhamrait SS, Maubaret C, Pedersen‐Bjergaard U, Brull DJ, Gohlke P, Payne JR, et al. Mitochondrial uncoupling proteins regulate angiotensin‐converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 2016;38(Suppl. 1):S107–18.
140 - Dong C, Della‐Morte D, Wang L, Cabral D, Beecham A, McClendon MS, et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque. PloS One. 2011;6:e27157.
141 - Dong C, Della‐Morte D, Cabral D, Wang L, Blanton SH, Seemant C, et al. Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology. International Journal of Stroke: Official Journal of the International Stroke Society. 2015;10:1247–52.
142 - Wang WY, Zee RY, Morris BJ. Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clinical Genetics. 1997;51:31–4.
143 - Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E, et al. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994;24:63–9.
144 - Tiret L, Blanc H, Ruidavets JB, Arveiler D, Luc G, Jeunemaitre X, et al. Gene polymorphisms of the renin‐angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d’Etude des Genes de l’Hypertension Arterielle Severe a moderee Essentielle. Journal of Hypertension. 1998;16:37–44.
145 - Morisawa T, Kishimoto Y, Kitano M, Kawasaki H, Hasegawa J. Influence of angiotensin II type 1 receptor polymorphism on hypertension in patients with hypercholesterolemia. Clinica Chimica Acta; International Journal of Clinical Chemistry. 2001;304:91–7.
146 - Stankovic A, Zivkovic M, Glisic S, Alavantic D. Angiotensin II type 1 receptor gene polymorphism and essential hypertension in Serbian population. Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003;327:181–5.
147 - Mottl AK, Shoham DA, North KE. Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: a HuGE review. Genetics in Medicine: Official Journal of the American College of Medical Genetics. 2008;10:560–74.
148 - van Geel PP, Pinto YM, Voors AA, Buikema H, Oosterga M, Crijns HJ, et al. Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension. 2000;35:717–21.
149 - Lim HS, Cho JY, Oh DS, Chung JY, Hong KS, Bae KS, et al. Angiotensin II type 1 receptor 1166A/C polymorphism in association with blood pressure response to exogenous angiotensin II. European Journal of Clinical Pharmacology. 2007;63:17–26.
150 - Chapman CM, Palmer LJ, McQuillan BM, Hung J, Burley J, Hunt C, et al. Polymorphisms in the angiotensinogen gene are associated with carotid intimal‐medial thickening in females from a community‐based population. Atherosclerosis. 2001;159:209–17.
151 - Sticchi E, Romagnuolo I, Sofi F, Pratesi G, Pulli R, Pratesi C, et al. Association between polymorphisms of the renin angiotensin system and carotid stenosis. Journal of Vascular Surgery. 2011;54:467–73.
152 - Plat AW, Stoffers HE, de Leeuw PW, van Schayck CP, Soomers FL, Kester AD, et al. Sex‐specific effect of the alpha‐adducin (G460W) and AGTR1 (A1166C) polymorphism on carotid intima‐media thickness. Journal of Hypertension. 2009;27:2165–73.
153 - Zhu S, Meng QH. Association of angiotensin II type 1 receptor gene polymorphism with carotid atherosclerosis. Clinical Chemistry and Laboratory Medicine. 2006;44:282–4.
154 - Zhang H, Sun M, Sun T, Zhang C, Meng X, Zhang Y, et al. Association between angiotensin II type 1 receptor gene polymorphisms and ischemic stroke: a meta‐analysis. Cerebrovascular Diseases (Basel, Switzerland). 2011;32:431–8.
155 - Stankovic A, Kolakovic A, Zivkovic M, Djuric T, Bundalo M, Koncar I, et al. Angiotensin receptor type 1 polymorphism A1166C is associated with altered AT1R and miR‐155 expression in carotid plaque tissue and development of hypoechoic carotid plaques. Atherosclerosis. 2016;248:132–9.
156 - Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, et al. Human microRNA‐155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3’ untranslated region: a mechanism for functional single‐nucleotide polymorphisms related to phenotypes. American Journal of Human Genetics. 2007;81:405–13.
157 - Haas U, Sczakiel G, Laufer SD. MicroRNA‐mediated regulation of gene expression is affected by disease‐associated SNPs within the 3′‐UTR via altered RNA structure. RNA Biology. 2012;9:924–37.
158 - Warnecke C, Mugrauer P, Surder D, Erdmann J, Schubert C, Regitz‐Zagrosek V. Intronic ANG II type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing. American Journal of Physiology Regulatory, Integrative and Comparative Physiology. 2005;289:R1729–35.
159 - Stankovic A, Zivkovic M, Kostic M, Atanackovic J, Krstic Z, Alavantic D. Expression profiling of the AT2R mRNA in affected tissue from children with CAKUT. Clinical Biochemistry. 2010;43:71–5.
160 - Kolakovic A, Stankovic A, Djuric T, Zivkovic M, Koncar I, Davidovic L, et al. Gender‐specific association between angiotensin II type 2 receptor ‐1332 A/G gene polymorphism and advanced carotid atherosclerosis. Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association. 2016;25:1622–30.
161 - Zivkovic M, Djuric T, Stancic O, Alavantic D, Stankovic A. X‐linked angiotensin II type 2 receptor gene polymorphism ‐1332A/G in male patients with essential hypertension. Clinica Chimica Acta; International Journal of Clinical Chemistry. 2007;386:110–3.
162 - Tousoulis D, Koumallos N, Antoniades C, Antonopoulos AS, Bakogiannis C, Milliou A, et al. Genetic polymorphism on type 2 receptor of angiotensin II, modifies cardiovascular risk and systemic inflammation in hypertensive males. American Journal of Hypertension. 2010;23:237–42.
163 - Johansson ME, Fagerberg B, Bergstrom G. Angiotensin type 2 receptor is expressed in human atherosclerotic lesions. Journal of the Renin‐Angiotensin‐Aldosterone System: JRAAS. 2008;9:17–21.
164 - Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT(2) receptor and tissue injury: therapeutic implications. Current Hypertension Reports. 2014;16:416.
165 - Matavelli LC, Siragy HM. AT2 receptor activities and pathophysiological implications. Journal of Cardiovascular Pharmacology. 2015;65:226–32.