Accelerated Atherosclerosis in Patients with Systemic Lupus Erythematosus and the Role of Selected Adipocytokines in This Process

Systemic lupus erythematosus (SLE) can affect various systems and organs. The most severe forms of the disease affect the kidneys, the central nervous system, and the heart. Cardiac and cardiovascular system diseases are inter alia caused by atherosclerosis, vasculitis, and thromboembolic events. Patients with SLE are at a higher risk of developing accelerated atherosclerosis. This process in SLE patients cannot be explained solely based on classical risk factors. Recently, some adipocytokines/adipokines have been indicated in the development of atherosclerosis, inflammation, and immune processes. It has also been postulated that adipokines might regulate the immune response and hence the atherogenic process. In this work, the factors contributing to accelerated atherosclerosis in SLE patients with special respect to vasculitis/vascular injury are presented, and selected adipocytokines, that is leptin, resistin, and adiponectin, with their relation to atherosclerosis and SLE, are under discussion.


Introduction
Systemic lupus erythematosus (SLE) is an organ-nonspecific autoimmune disease, more prevalent in young women than in men. It is characterized by periods of varying activity, sometimes even spontaneous remission. However, there can also be life-threatening disease flares, especially in those patients who undergo incorrect treatment.
The mechanisms of accelerated atherosclerosis in SLE patients are not fully understood and remain controversial. Its development cannot be accounted for based on traditional risk factors such as age, male sex, arterial hypertension, abnormalities in serum lipids, smoking, diabetes mellitus, obesity, and abnormal results of laboratory tests including high levels of C-reactive protein (CPR), fibrinogen, and homocysteine [4,11,[29][30][31][32][33][34]. Other causative factors that might promote accelerated atherosclerosis should also be considered [35].
It has been suggested that atherosclerosis could be caused by an immune reaction against autoantigens at the endothelial level, which include oxidized low-density lipoprotein (LDL) and heat shock proteins (HSP) 60/65. Endothelial dysfunction plays a key role. It has also been speculated that immune mechanisms might be responsible for conversion of stable to instable plaque with resultant rupture [36].
Thus, it is not surprising that several autoimmune diseases, for example, SLE and antiphospholipid syndrome, are considered to raise the risk of CAD [37]; nevertheless, the precise mechanism is yet to be defined [38]. Multiple researchers believe that atherosclerosis is associated with immune responses [37,39,40]; it should be emphasized though that considering atherosclerosis as a solely autoimmune condition would be an oversimplification since metabolic disorders and hemodynamic factors are also involved in its development [41].
Although there is a lot of evidence that inflammation plays a central role in atherosclerosis, its pathogenesis is also associated with other risk factors often connected with SLE, that is arterial hypertension (especially renal hypertension), prolonged exposure to high doses of glucocorticoids (which, apart from having a beneficial anti-inflammatory action, also influence blood pressure and glucose metabolism), lupus-associated antiphospholipid syndrome, diabetes mellitus, and hypercholesterolemia [23,25]. It should be noted that a regimen of ≤ 10 mg prednisone daily is considered safe in this respect [25]; however, the problem of metabolic disorders seen in SLE patients and its relation to glucocorticoid doses has not been satisfactorily elucidated. Contrary to steroids, antimalarial drugs used in SLE patients have a beneficial effect on their lipid profile.
Patients with SLE also exhibit other metabolic disturbances that may promote accelerated atherosclerosis and accelerated CAD. These include hypertriglyceridemia, high homocysteine levels, and early menopause [25].
The multifactorial etiology of atherosclerosis makes it difficult to unambiguously determine why SLE patients develop atherosclerotic lesions earlier in life and more frequently than the general population. Researchers are often confronted with inconsistent results [23,42]; hence, it has been suggested SLE might be considered an independent risk factor for atherosclerosis including CAD [24,[43][44][45] and CVD [23].
The factors underlying the atherosclerotic process undoubtedly comprise pro-inflammatory cytokines, antiphospholipid antibodies, antiendothelial cell antibodies (AECAs), and antineutrophil cytoplasmic antibodies (ANCAs), all acting directly on blood vessels or forming deposits of immune complexes. Monocyte chemotactic protein-1 (MCP-1) [7] is also involved; its higher concentrations were revealed in the blood of our study participants with mild-to-moderate SLE [46]. Other researchers investigated the relationships between atherosclerotic plaques in the carotid arteries, antiphospholipid antibodies, and peripheral blood leukocyte count, an established indicator of inflammation [25]. There is also a spectrum of vascular abnormalities in SLE, resulting from adverse effects of several drugs or induced by infections, etc. [15].
It is important to note that vascular injury may develop not only due to an inflammatory condition but also as a result of non-inflammatory factors including environmental influences (toxicity, medication, or micro-organisms), neoplastic process, etc. [14]. Vascular disease in SLE patients can occur due to a combination of different pathological processes, for example, atherosclerosis, clotting disorders, and systemic vasculitis associated with vascular wall injury (especially endothelial dysfunction), caused by an autoimmune process [24,28].
SLE patients most typically exhibit cutaneous vasculitis; systemic vasculitis develops in 10-18% of these patients and, as a life-threatening condition, may require aggressive therapy [14,15].
Recently, it has been suggested that adipokines might play a causative role in the development of atherosclerosis, inflammatory, and immune processes [47]. These factors, secreted by the white adipose tissue, have autocrine-like actions, locally affecting adipocyte biology. They also act as endocrine factors that regulate systemic processes, for example, food intake, insulin sensitivity, bone growth and energy homeostasis, and affect development of obesity and metabolic syndrome [40,48]. Adipokines have been indicated in the link between immune response and atherosclerotic process [49].
Since patients with SLE develop metabolic syndrome, insulin resistance, dyslipidemia, or hypertension more frequently than the general population [50][51][52][53][54], the interest in the adipose tissue is justified in the group of rheumatic diseases [55,56]. Identification of mechanisms common to inflammation and CVD might be of considerable interest especially in the context SLE, which is, potentially, a model disease for gaining a deeper insight into such mechanisms [13]. Generally, the relationship of adipokines to inflammation and coronary atherosclerosis in patients with SLE has not been fully elucidated [57]; for example, it has not been determined whether adiponectin concentrations in SLE result from metabolic disorders or inflammatory processes and nor has it been determined whether adipokine abnormalities associated with connective tissue diseases contribute to disease development or are caused by inflammation induced by other pro-inflammatory factors [58].

Adipocytokines and their relation to atherosclerosis and systemic lupus erythematosus
White adipose tissue is a loose connective tissue composed of adipocytes and also containing adipocyte precursors, immune system cells fibroblasts, and other cell types [59]. Previously, this tissue had been considered an energy store (triglycerides) but now it is known to produce a number of biologically active substances that act at autocrine, paracrine, and endocrine levels. They regulate homeostasis through regulation of food intake, energy balance, lipid, and carbohydrate metabolism. They also modulate the insulin effects, angiogenesis, and vascular remodeling, regulate arterial pressure, affect inflammatory processes as well as associated immune response, and have metabolic effects including an impact on the development of atherosclerosis [47,50,57,[59][60][61][62][63]. Since the structure of these substances resembles that of the cytokine family, they have been referred to as adipocytokines or adipokines [60]. Their multifunctionality underlies the relationship between white adipose tissue, metabolic disorders, and autoimmune diseases [59]. Actions of selected adipokines are summarized in Table 1.
The role of adipokines in atherosclerosis deserves particular attention as they modulate inflammatory processes and initiate its development [60]. Adipokines may constitute a link between impaired insulin sensitivity, obesity, chronic inflammation, and atherosclerosis in patients with SLE [57,64]. It has been speculated that altered serum/plasma levels of adipokines in SLE might be related to coronary atherosclerosis, insulin resistance, and the inflammatory process [57]; however, these correlations need to be further explored and documented [65]. A deep insight into the mechanisms of adipokine actions would help develop new therapies-also for autoimmune disorders [58,66].
It is assumed that resistin or leptin have pro-inflammatory and proatherosclerotic effects; they have also been implicated in insulin resistance [57,67]. Conversely, adiponectin has an inverse association with inflammatory states, atherosclerosis, and insulin resistance [68]; hence, independent of traditional risk factors, low level of adiponectin might also contribute to the development of the abovementioned diseases [57,69]. However, other studies did not confirm these causative associations [69][70][71] with respect to total adiponectin levels but only to some adiponectin isoforms determined in the serum [69]. The reported research results are therefore inconsistent.
Resistin plays an important role in the inflammatory process, but its amount in adipocytes is quite small. Greater resistin concentrations have been found in adipose tissue monocytes and macrophages and peripheral blood monocytes [72,73]. It is also present in neutrophils and is capable of inducing the production of IL-6 and TNFα [42,[74][75][76]. These facts may indicate pro-inflammatory properties of resistin [73]. Patients with severe inflammatory disease exhibit significant increases in plasma resistin [77]. It is also noteworthy that endothelial cells exhibit sensitivity to resistin.

Resistin Adiponectin Leptin
Obesity Obesity Insulin resistance Although the role of resistin in SLE has not been fully determined [57,58], its concentrations in the peripheral blood of SLE patients are elevated and have been found to correlate with inflammatory markers, glomerular filtration rate, and glucocorticoid therapy [75,78]. However, other studies did not reveal significant differences in serum resistin between patients with SLE and control participants [78]. Hence, reports on resistin levels in SLE patients are not consistent and its role remains to be elucidated.
It has been argued that resistin concentrations might be predictive of coronary atherosclerosis, acute coronary events, and associated mortality [74,78,79]. It has been hypothesized that resistin secreted from macrophages in atheromas could affect vascular cell function and promote atherosclerosis [80]. Furthermore, it has been suggested that the levels of serum resistin might help determine the severity of myocardial ischemia [81], and its reduction could possibly reduce the risk for CVD [47]. It has also been speculated that this adipokine is more related to the inflammatory process and atherosclerosis than to obesity and insulin resistance [47].
Plasma leptin is known to be proportional to the total amount of adipose tissue, and therefore it is directly related to obesity and associated CVDs including atherosclerosis. Leptin exerts its atherogenic effects via induction of endothelial dysfunction, stimulation of inflammatory response, oxidative stress, platelet aggregation, migration, hypertrophy, and proliferation of vascular smooth muscle cells [82]. It regulates blood pressure and this is probably independent of body adiposity [83]. Plasma leptin concentration correlates with markers of subclinical atherosclerosis such as extracranial carotid intima-media thickness and coronary artery calcification. Beltowski [82] speculates that inhibition of leptin activity might slow down the progression of atherosclerosis in obese individuals with hyperleptinemia.
There are also data on the involvement of leptin in the immune response [77] and its modulatory effect on monocytes/macrophages, neutrophils, basophils, eosinophils, natural killer cells (NK), and dendritic cells [63,84]. It has also been indicated in lymphocyte reactivity [85]. As already mentioned, leptin is considered a pro-inflammatory adipokine; therefore, changes in its plasma levels observed in SLE patients are not surprising. Leptin modulates the cardiovascular risk in these patients [86], and several authors have suggested that the adipokine might act as an independent risk factor for CVD [68].
Patients with SLE had higher plasma leptin compared to the control [49,57,87,88], but clinical relevance of leptin level changes in autoimmune disorders remains unclear [87]. Several researchers believe that leptin is involved in the pathogenesis thereof [88,89]. The evaluation of leptin concentrations in SLE patients with correction for BMI (body mass index) also revealed higher levels in the study group [42]. However, other authors concluded that leptin levels in SLE patients were lower or comparable to those found in healthy controls [90,91].
Adiponectin, the major product of adipocytes, functions as an autocrine/paracrine factor within the adipose tissue and exerts endocrine effects on distant tissues thus influencing whole-body metabolism [92].
The role of adiponectin in SLE remains controversial. Several researchers observed an increase in adiponectin concentration in SLE patients [57,91], while others did not find differences compared to the control [50,58]. However, plasma adiponectin levels tend to be higher in patients with renal SLE in comparison to healthy controls and patients with nonrenal SLE [93].
Although the role of adiponectin in SLE pathogenesis has not been fully elucidated [86], higher local and/or systemic concentrations of this adipokine have been noted in chronic inflammatory conditions including SLE [94]. Nevertheless, processes leading to adiponectin levels elevation in chronic inflammatory/autoimmune diseases are still to be clarified [94].
The significance of adiponectin in atherosclerosis also needs clarification [72]. It was postulated that the anti-inflammatory effects of adiponectin were associated with the inhibition of pro-inflammatory cytokines, decreased leukocyte adhesion, and enhanced production of anti-inflammatory cytokines [95]. Adiponectin mediates inhibition of macrophage phagocytosis and decreases the production of IL-6 and TNF. It strongly inhibits B-lymphopoiesis, reduces T-lymphocyte response, and induces the production of anti-inflammatory agents (e.g., IL-10) in human monocytes, macrophages, and dendritic cells [62,63]. Adiponectin also suppresses monocyte adhesion to endothelial cells as well as migration and proliferation of smooth muscle cells [30]. Hence, it may exert a beneficial effect in the metabolic syndrome and coronary heart disease. Low adiponectin concentrations have been found to enhance insulin resistance and the risk for coronary heart disease. It is noteworthy, though, that, contrary to its protective role with respect to obesity and vascular disease, adiponectin seems to have pro-inflammatory effects in joint diseases [58,62,63].
Summing up, it should be noted that metabolic disorders frequently seen in patients with SLE might result from the disease itself or genetic influences/long-term treatment. Patients with SLE also tend to more frequently develop a classic metabolic disease, that is obesity, which is associated with chronic, although not severe, inflammatory conditions. The latter has an impact on insulin resistance-related type 2 diabetes as well as on atherosclerosis and ischemic heart disease.