IntechOpen

Home > Books > Non-Proteinogenic Amino Acids

Open access peer-reviewed chapter

Is Homocysteine a Marker or a Risk Factor: A Question Still Waits for an Answer

Written By

Cristiana Filip, Elena Albu, Hurjui Ion, Catalina Filip, Cuciureanu Magda, Radu Florin Popa, Demetra Gabriela Socolov, Ovidiu Alexa and Alexandru Filip

Submitted: 15 September 2018 Reviewed: 02 October 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.81799

Non-Proteinogenic Amino Acids IntechOpen
Non-Proteinogenic Amino Acids Edited by Nina Filip

From the Edited Volume

Non-Proteinogenic Amino Acids

Edited by Nina Filip and Cristina Elena Iancu

Book Details Order Print

Chapter metrics overview

1,301 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Homocysteine, a non-proteinogenic sulfur-containing amino acid, was discovered in 1932, and 30 years passed until, in 1969, for the first time, its involvement in pathology was reported. It was only in the last two decades that homocysteine has become a subject of scientific interest and has begun to be intensively studied. A large number of scientists consider homocysteine as an independent risk factor particularly for cardiovascular disease, while others indicate homocysteine as a marker of this disease. Both sides bring scientific arguments for their opinions, yet the dilemma of homocysteine characterization still persists. Although the reported studies do not lead to a unique answer, it is generally accepted that homocysteine is associated with vascular dysfunction. Numerous scientific data show that the link between homocysteine and inflammation is achieved via the reactive oxygen species (ROS) pathway. The latest data indicate hydrogen peroxide as a possible messenger in cellular signaling in physiological or pathological processes and present the consequences of disturbing the oxidation-reducing balance. In this chapter, we present the latest scientific evidences gathered from the literature for both hypotheses regarding homocysteine involvement in pathology, and we propose a possible mechanism of action for homocysteine, based on our preliminary (yet unpublished) work.

Keywords

  • hyperhomocysteinemia
  • ROS
  • inflammation
  • cell signaling
  • protein-tyrosine phosphatases

1. Introduction

Homocysteine (Hcy) is a non-proteinogenic amino acid that is formed in the human body in methionine metabolism. Although not forming proteins, homocysteine participates in major processes such as transmethylation, cysteine (Cys) formation, transsulfuration, etc. In the transmethylation process, homocysteine is an intermediate that allows the formation of compounds with a major metabolic role such as adrenaline, lecithin, creatine, etc. Cysteine formation, via homocysteine, is a very important process because Cys is a vital amino acid to stabilize the spatial conformations of proteins, to form the most important antioxidant agent in the body named glutathione, or to detoxify harmful compounds.

Over the past 40 years, homocysteine has come to the clinicians’ attention because its high levels in blood have been associated with high risk of mortality and morbidity in many illnesses, particularly cardiovascular diseases. Patients with high levels of Hcy, also called hyperhomocysteinemia (HHcy), develop thromboembolism, premature atherosclerosis, mental retardation, bone fragility, eyes disease, and even miscarriage.

It is obvious that Hcy is related to the pathological phenomenon but the way it intervenes has not yet been elucidated. Moreover, there are researchers who believe that homocysteine indicates an already altered state [1] while others consider it a factor triggering the alteration of some functions [2]. Both opinions are based on scientific arguments, and although the debate continues, most researchers agree that there is an unquestionable link between homocysteine and vascular endothelial dysfunction [3, 4, 5]. Endothelial dysfunction may have several causes, but the major cause is inflammation. Inflammation is the vital process by which organisms respond to aggression. In the inflammatory process, a large number of pathways are activated to remove aggression and restore homeostasis [6, 7, 8]. Complex structures such as cells, proteins, but also small molecules such as reactive species, that are capable of rapidly signaling changes in homeostasis, are involved in this process. The activities of these structures need to be coordinated, and the latest data indicates that the inflammasome is responsible for this task. Recent data have found links between Hcy activity and inflammation [9]. In this chapter we present these new data that connect Hcy, inflammation, cell signaling, and reactive species.

As a conclusion, current data indicates Hcy as an amino acid that certainly plays a role in pathology, a role that needs to be elucidated.

Advertisement

2. Homocysteine metabolism

A short presentation of the homocysteine metabolism indicates two major pathways of transformation: the transmethylation pathway and the transsulfuration pathway (Figure 1).

Figure 1.

Main pathways of homocysteine transformation.

Transmethylation pathway converts Hcy to methionine through a chain of reaction that involve the participation of methylenetetrahydrofolate reductase (MTHFR), folic acid, vitamin B12, and methionine synthase (MS).

Transsulfuration pathway converts Hcy to cystathionine in the presence of the cystathionine beta-synthase (CBS) and vitamin B6. Figure 1 highlights the role of tetrahydrofolate (FH4), the active form of folic acid, B12, and pyridoxal phosphate (PLP), the active form of vitamin B6 in the Hcy metabolism. A minor pathway, not shown in this figure, uses betaine to convert homocysteine to methionine.

The general methionine/homocysteine metabolism highlights the two major causes that generate HHcy: first, the enzymatic deficiencies of the enzymes acting in Hcy metabolization and, second, the nutritional deficiencies in vitamin cofactors. This last observation is the base of the therapeutic approaches that uses vitamin administration in order to decrease the homocysteine levels.

The normal concentration of homocysteine in human blood is 5–15 μM. HHcy is classified according to clinical consequences as being moderate at 16–30 μM, intermediary at 31–100 μM, and severe above 100 μM [10]. HHcy caused by the lack of vitamins is not commonly found in medical practice and it is easy to cure. The most common cause of HHcy is the enzymatic defect of different enzymes acting in this metabolism.

Advertisement

3. Homocysteine in pathology

3.1. Cardiovascular diseases

Currently, it is widely accepted that levels of Hcy, even at concentrations slightly higher than normal, are related to the risk of cardiovascular disease. Clinical studies indicate that a 5 μM increase in Hcy levels is equivalent to a 20 mg/dL increase in blood cholesterol [11, 12], which virtually doubles the cardiovascular risk. This suggests that between levels of Hcy and atherosclerosis there is a better correlation than between the cholesterol levels and atherosclerosis [13, 14]. However recent data [2, 15] show that a surprising 30% of cardiovascular mortality occurs in patients who do not present conventional risk factors as high LDL, hypertension, smoking, or obesity. This raises the question whether Hcy is an independent risk factor or it is a marker of a lesion process.

3.2. Diabetes

Hyperhomocysteinemia is considered a higher risk for patients with diabetes than nondiabetic patients. An exponential increase in vital risk has been demonstrated in patients presenting HHcy associated to diabetes [16, 17, 18]. The increase in Hcy levels noticed in diabetes is believed to be due to the degree of diabetes-induced nephropathy [19, 20, 21]. Thus, high levels of Hcy are found in kidney failure. This data suggest more for a marker role of homocysteine rather than a risk factor.

3.3. Neurological diseases

Seshadri [22] has shown that HHcy is associated with Alzheimer’s disease and that it doubles the risk of developing the disease in patients with elevated levels of homocysteine as compared to those with normal levels. Although the mechanism that links Hcy to Alzheimer’s is unknown, it is supposed that HHcy toxicity to neuronal cells is caused by possible neuronal damage following excessive stimulation caused as result of chronic central nervous system ischemia [23, 24, 25].

3.4. Bone fragility

Increased levels of homocysteine were correlated with increased risk of bone fractures in the elderly [26, 27, 28, 29, 30, 31]. It seems that Hcy does not affect bone density but rather affects the structure of collagen by interfering in the transversal linkages between the collagen fibers. Thus, Hcy intervenes in tissue fortification showing more a risk factor role.

3.5. Miscarriage

Research studies notify that HHcy can be generated by the specific mutation in MTHFR. This inherited deficiency lead to a 3.3-fold increase in the risk of miscarriage in a sample group of 185 Caucasian women [32, 33]. Literature also specifies that associations between MTHFR C667T mutations to factor V Leiden and prothrombin gene mutations were identified in patients having recurrent miscarriages [34].

Advertisement

4. Homocysteine involvement in the endothelial function

The presented data show that in high concentration Hcy certainly plays a role in pathology. A large number of recent studies indicate that Hcy is an independent risk factor in cardiovascular disease [2, 35]. However, other studies indicate Hcy as a marker of this disease [1]. Although the reported studies do not lead to a unique answer regarding homocysteine role, it is generally agreed that homocysteine is connected to the vascular dysfunction. As a consequence, the investigation of HHcy leads to the investigation of endothelial dysfunction. Normal endothelial function consists in maintaining the vascular relaxation and the anticoagulant status. Any aggression on the endothelial homeostasis leads to changes in vascular morphology, tonicity, coagulability, etc. The intensity and time span of aggression determine the transition from a normal to a pathogenic transformation.

4.1. Endothelial dysfunction

Vascular endothelium modulates vascular tonicity by secreting a large group of vasoactive molecules such as vasodilators (e.g., NO, prostacyclin) and vasoconstrictors (e.g., endothelin, thromboxane). The ratio of these compounds showing antagonist action dictates the final vascular tonicity, and under pathological conditions, additional stimulants (mediators of inflammation) cause severe changes in vascular behavior.

Nitric oxide (NO) a natural free radical is synthesized by nitric oxide synthases (NOS) from L-arginine by many types of cells including the endothelial cells. Nitric oxide that is synthesized by endothelial nitric oxide synthase (eNOS) promotes vasodilatation; inhibits platelet activation, adhesion, and aggregation; prevents smooth muscle proliferation; and modulates endothelial-leucocytes interaction [36]. Homocysteine diminishes NO bioavailability through various processes that are, at least partially, based on oxidative mechanisms. The current literature presents three mechanisms proposed to explain the decrease in NO bioavailability in the presence of elevated levels of Hcy. The first mechanism indicates that Hcy reacts with nitric oxide to form S-nitroso-homocysteine [36, 37]. The second one considers that NO bioavailability is blocked by sequestration following reactions with other radical species. NO is trapped by superoxide to form peroxynitrite, thus being inactivated [38, 39]. The third mechanism assumes that NO synthesis is decreased by NO-synthase inhibition by asymmetric dimethylarginine (ADMA), a potent inhibitor of the enzyme produced by the degradation of methylated proteins [40]. Increased ADMA concentration was identified in an HHcy status [41]. These mechanisms are found widely presented in our previous work [42].

Eicosanoids represent a group of compounds directly involved in vascular function. They act as paracrine hormones and mediate the inflammatory response. This group includes prostacyclin (PGI2), a compound with vasodilating activity, and thromboxane TXA2, a compound with vasoconstrictive activity. Prostacyclin or prostaglandin PGI2, produced by epithelial cells, prevents platelet aggregation, decreases proliferation of smooth muscle cells, decreases pro-inflammatory cytokines (↓IL-1 and IL6), and exerts antimitogenic activity (↓VEGF and TGF-β). On contrary TXA2 promote the thrombosis and vascular constriction. In the chain of reactions that generates eicosanoids, some are of the oxidative type so they generate reactive species. Thus, the balance between these paracrine hormones is very important for the vascular homeostasis. Research data show that HHcy is considered as a factor that prevents vasodilation, promotes vasoconstriction, and increases the risk of thrombosis, thus inducing vascular injuries [43]. In vitro studies have demonstrated that HHcy induces the release of arachidonic acid, precursor of eicosanoids, including TXA2 [44].

Endothelins are vasoconstricting peptides mainly produced by the endothelium. They constrict blood vessel promoting high blood pressure. In addition to its vasoconstrictor effects, isoform endothelin-1 (ET-1) influences cell growth, thus being involved in atherosclerosis. Epithelial cells regulate ET-1 levels in response to hypoxia, oxidized species of LDL, or pro-inflammatory cytokines. Endothelins (ET-1, ET-2, ET-3) act on two receptors that have different locations and whose activation triggers different effects: vasoconstrictive effect through ETA receptors located in smooth muscle cells [45] and vasodilation and NO release through ETB receptors located on endothelial cells. Recent data show that HHcy results in the upregulation of ETA receptor expression and high blood pressure in rats [46] while decreasing ET-1 production in endothelial cells, thus impairing NO and prostacyclin production and consequently the vasodilatation [47]. Thus, HHcy disturbs the ratio between vasodilators and vasoconstrictors promoting endothelial dysfunction [48].

Advertisement

5. Homocysteine mechanism of action

In the endothelial dysfunction, the inflammation process is a key step, and the reactive species are present at the site of inflammation, playing multiple roles, including defense, annihilation, or cellular signaling. In this chain of events, HHcy interferes somewhere with the endothelial normal function. There are several generally accepted mechanisms for Hcy-dependent endothelial dysfunction: reactive oxygen species [49], inflammatory response [50], or thrombotic phenomenon [51]. These mechanisms will be presented below along with scientific evidence for each of them.

5.1. Hyperhomocysteinemia involvement in oxidative stress

Numerous researches point ROS as the potential mediators for the effects of HHcy. Generation of reactive species is considered to trigger a cascade of events leading to release of pro-inflammatory cytokines, activation of adhesion molecules, generation of intracellular messengers that activate intracellular enzymes, and cellular responses including gene activation/repression [52, 53, 54]. Many studies demonstrate that HHcy generates reactive species directly or through autoxidation [55, 56]. ROS species found in HHcy was indirectly assessed through the measurement of antioxidative enzyme activity [57, 58, 59]. In our previous work, we have found that HHcy triggers the generation of hydrogen peroxide and that high levels of homocysteine experimentally induced (by methionine loading in rat) diminish more the total antioxidant capacity inside the erythrocytes rather than in plasma [60, 61].

5.2. Hyperhomocysteinemia involvement in inflammation

Recent studies [7, 8] had advanced the idea that Hcy triggers vascular damage by promoting an inflammatory response followed by immediate effects on the vascular wall or by delayed effects on proteins and DNA structures. The inflammatory phenomenon represents the vascular tissue response to lesion agents (chemical/physical or biological) [6]. The inflammatory response consists in two actions: removal of the lesion agent and initiation of the healing process. The acute inflammation predominates the local vascular response characterized by the presence of fast-acting and low half-life components (leucocytes). In the chronic inflammation, there is a progressive change in the types of cells present at the lesion site, characterized by the dominant presence of macrophages. The crucial phase is the destruction of pathogens. This phase takes place in monocytes/macrophages and neutrophils in the respiratory burst where the reactive oxygen species are generated. ROS are as damaging to pathogens as they are to the host’s tissue. Consequently, chronic inflammation is accompanied by tissue destruction. Macrophages/neutrophils are not the site for respiratory burst only, but they also secret and/or trigger the secretion of specific compounds such as cytokines. The discovery of interleukins had introduced the concept of systemic inflammation. This type of inflammation is characterized by the fact that tissue destruction is not limited to a certain tissue but involves endothelium and other organs also. In systemic inflammation, elevated levels of chemical mediators such as interleukins (IL-6, IL-8, and TNFα) are associated with atherosclerosis and diabetes [62, 63, 64]. Recently, it has been found that HHcy is associated to inflammatory markers IL-6 and TNFα [65, 66, 67, 68].

The cells of the innate immune system continually survey the extracellular environment in order to detect the “danger” signal. To achieve this function, immune cells develop receptors that act as sensors for the “invaders.” Following the foreign detection, a group of actions must be initiated and coordinated, task being undertaken by the inflammasome. Inflammasomes are key signaling platforms that act as a checkpoint that controls and regulates the inflammatory response. It consists of multi-protein complexes that assemble by pattern-recognition receptors after the detection of a “danger “signal in the cytosol of the host cell. The protein association represents the activation stage of the inflammasome that triggers the signal of inflammation which is the caspase 1 and caspase 11 activation. Activated caspases initiate the highly pro-inflammatory cytokines’ interleukin-1β (IL-1β) and IL-18 production, and finally an inflammatory form of cell death termed pyroptosis is triggered. The intracellular control of the inflammasome assembly is exerted via ion fluxes, free radicals, and autophagy. Latest data indicate the inflammasome activation as a possible mechanism for homocysteine involvement in inflammation and in programmed cell death in endothelial cells [69]. Current literature also demonstrates that the activation of inflammasomes (NLRP3 complex) represent a key step in HHcy-aggravated atherosclerosis [9].

5.3. Hyperhomocysteinemia involvement in thrombogenesis

HHcy promotes thrombosis by a mechanism that integrates the already presented processes of oxidation and decreases the NO bioavailability with the modification of some specific proteins acting in the coagulation and fibrinolysis pathway. Literatures show that homocysteine initiates structural modifications of these proteins, modifications that will impair their normal functions. Such proteins include the tissue plasminogen activator (tPA), atherogenic factor lipoprotein(a) (Lp(a)), the complex thrombomodulin-thrombin, and DNA proteins.

The tPA is a serine protease that converts plasminogen to fibrinolytic protein plasmin. Hcy forms disulfide bridge with annexin II (an important receptor for tissue plasminogen activator in endothelium), thus blocking tPA binding to this protein. As a result, tPA activity is impaired, plasmin generation is diminished, and fibrinolysis activity is decreased [70].

Activation of plasminogen depends on the binding of fibrin as a cofactor. Lipoprotein (a) is an atherogenic lipoprotein which competitively binds to fibrin, thus preventing activation of plasminogen. Hcy favors lipoprotein-a binding to fibrin, which ultimately leads to decreased fibrinolysis [71]. HHcy added to a dyslipidemia profile results in increased risk of thrombosis.

Protein C is another serine protease present in blood as zymogen. Upon activation it exerts important role in anticoagulation, inflammation, and also cell death. The complex thrombomodulin-thrombin activates protein C, thus inhibiting the thrombotic process. Hcy impairs the complex thrombomodulin-thrombin activity by forming disulfide bridges with both thrombomodulin and protein C. As a consequence, the thrombotic process is promoted [72]. These mechanisms are found widely presented in our previous work [42].

5.4. Hyperhomocysteinemia involvement in cellular signaling

The survival of the cell is by default linked to its ability to remove any type of aggression/lesion and to restore the initial healthy structure. In this process, cells develop a network of systems that is capable to communicate, to mobilize defense/healing structures, or to memorize information about the type of aggression. In this process, complex structures and small molecules are equally involved, together being able to signal any changes in homeostasis. Reactive species of oxygen and nitrogen as well as active peptides (cytokines) produced at the site of inflammation by neutrophils or monocytes/macrophages are small molecules capable of rapid signaling. They promote vascular changes and open the inter-endothelial junctions thus allowing the migration of inflammatory cells across the endothelial barrier. All the activities related to inflammatory response are coordinated by chemical signaling through reactive species signals or active peptides (cytokine) [73].

The link between reactive species and inflammation is now well documented. On the other hand, current data associate Hcy with both inflammation and reactive species. The factor that puts together all these components is not fully elucidated. Over the past two decades, many scientific evidences show that ROS serve in physiological as well as pathological processes [74, 75]. Normal levels of reactive species act as signaling molecules to regulate biological and physiological processes, while their accumulation is strongly associated with oxidative stress [76]. Current scientific data indicate that among reactive oxygen species hydrogen peroxide is the most likely secondary messenger [77]. Early data had signaled that exogenously added H2O2 could mimic growth factor activity and that the growth factors could stimulate the endogenous production of H2O2 within cells. [78, 79, 80]. A major role in cell signaling that promotes cell proliferation, nutrient uptake, and cell survival is realized by the activation of the protein-tyrosine kinases class which includes both tyrosine kinases (Src, Ras, JAK2, Pyk2, PI3K) and mitogen-activated protein kinases (MAPK) (Figure 2).

Figure 2.

General signal pathway activated by ROS (modified from [81]), PKC = protein kinase, MAPK = mitogen-activated protein, JNK = c-Jun N-terminal kinases, ERK = extracellular signal-regulated kinases, NFκB = nuclear factor κB, AP-1 = activator protein-1, HIF-1 = hypoxia-inducible factor-1 C [42]. More details about the cellular response in ROS and other radical and nonradical species attack on oxidative events can be found in [82, 83, 84].

These signal transduction pathways use receptors with intrinsic tyrosine kinase activity (RTK) which leads to the phosphorylation of specific tyrosine residues located on tyrosine kinase proteins. Literatures show that hydrogen peroxide is required for optimal activation of protein-tyrosine kinases [85]. In the same time, hydrogen peroxide transiently inhibit protein-tyrosine phosphatases (PTPs) through the reversible oxidization of their catalytic cysteine [86], thus suppressing protein-tyrosine kinases dephosphorylation [87]. Thus, the activity of MAPK kinases is negatively regulated by protein-tyrosine phosphatases as depicted in Figure 3.

Figure 3.

Hydrogen peroxide role in protein-tyrosine kinases regulation. In normal/low concentration, H2O2 regulates PTPs activity by promoting the reversible oxidation of the Cys residues. At high concentration of H2O2, PTPs becomes irreversibly inactive and, as a consequence, tyrosine kinase proteins involved in cell proliferation (MAPK) remain blocked on active form. TRK = receptors with intrinsic tyrosine kinase activity; and PTP = proteon-tyrosine phosphatases.

Protein-tyrosine phosphatases are specific proteins that contain cysteine residues at their active site. These enzymes remove a phosphate group attached to a tyrosine residue (such in MAP kinases), using a cysteinyl-phosphate enzyme intermediate. Latest literature data [88, 89] show that the activity of protein-tyrosine phosphatases is regulated by the reversible oxidation of cysteine residues. In the reversible oxidation, the PTPs activity results in temporarily dampening of mitogenic signaling [84, 90]. Protein-tyrosine phosphatases can suffer an irreversible oxidation to their thiol groups, in the presence of high H2O2 levels, [91]. As a result, their function is blocked and the mitogen signal remains continuously activated (Figure 3).

Cysteine is unique among the amino acids because it is the only proteinogenic amino acid containing a free SH group. The mechanism of redox signaling involves reversible H2O2-mediated oxidation of cysteine residues within proteins [92]. During redox signaling low/normal concentration of H2O2 (nM range) oxidizes the thiol group of cysteine residues to sulfenic form (Cys-SOH). As the concentration of H2O2 gradually increases, the sulfenic form transforms to sulfinic (SO2H) and sulfonic (SO3H) forms, respectively. Unlike sulfenic modifications, sulfinic and sulfonic are irreversible transformations. As a consequence, high levels of H2O2 can trigger the irreversible oxidation of cysteine group.

Considering the above data, it is possible that Hcy, a H2O2 generator according to scientific data, may interfere in this signaling process promoting mitogenic activity.

Moreover, Hcy is very similar in structure to cysteine. Like cysteine, Hcy is an amino acid containing a free SH group. This makes possible the occurrence of disulfide bridges between the two amino acids similar to those existing between cysteine residues in some particular concentration of hydrogen peroxide. In our opinion (preliminary work, unpublished data), this may be a possible mechanism of homocysteine involvement in cell signaling that must be investigated (Figure 4).

Figure 4.

Possible mechanism for hyperhomocysteinemia to intercept the protein-tyrosine phosphatase regulation through disulfide bridge formation. TRK = receptors with intrinsic tyrosine kinase activity; PTP = proteon-tyrosine phosphatases; and HHcy = hyperhomocysteinemia.

All the scientific evidence presented above suggest Hcy as a risk factor for the vascular/endothelial dysfunction.

Instead some scientists investigate Hcy from the opposite point of view [93] and consider HHcy as a marker of an already altered vascular state rather than a risk factor. These authors consider that hypertension and atherosclerosis reach the stage where kidney function is severally impaired and Hcy removal is diminished and, consequently, its concentration rises in the blood. Atherosclerosis and hypertension are silent diseases that develop years before a vascular event occurs. The disease is accompanied by a silent decline in renal function and, as a consequence, total clearance including that of homocysteine diminishes. Thus, vascular disease contributes to the elevation of circulating Hcy as result of the progressive decline in renal function, and HHcy in fact reflects the severity of atherosclerosis. Thus, HHcy becomes a signal that the atherosclerotic disease reaches an irreversible stage.

Regardless of the classification of homocysteine as a risk factor or marker, its involvement in pathology is certain, and its role needs to be elucidated.

Advertisement

6. Conclusion

The study of homocysteine began when its association with cardiovascular disease was discovered. Further studies revealed its association with vascular dysfunction, and then Hcy was linked to the inflammatory phenomenon. Recently, as studies advanced, the homocysteine involvement in inflammation has been identified. The inflammatory process in turn is related to the activity of reactive species, and recent data indicate protein-tyrosine phosphatases as key factors in regulating intracellular signaling pathways. These proteins allow regulation because they can undergo reversible oxidation phenomena due to the presence in their structure of cysteine residues bearing SH groups. The structural similarity of Cys with homocysteine draws attention to the possibility that Hcy may interfere with cysteine functions. In conclusion, the recent association of Hcy with both inflammation and the reactive species involved in cellular signaling indicates that homocysteine remains a topic of interest and attention in current research. It is obvious that HHcy is an issue of interest in contemporary medicine.

References

  1. 1. Zhang S, Yong-Yi B, Luo LM, Xiao WK, Wu HM, Ye P. Association between serum homocysteine and arterial stiffness in elderly: A community-based study. Journal of Geriatric Cardiology. 2014;11(1):32-38
  2. 2. Salemi G, Gueli MC, Vitale F, et al. Blood lipids, homocysteine, stress factor and vitamins in clinically stable multiple sclerosis patients. Lipids in Health and Disease. 2010;9(1):19
  3. 3. Hassan A, Hunt BJ, O’Sullivan M, Bell R, D’Souza R, Jeffery S, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127(1):212-219
  4. 4. Pushpakumar S, Kundu S, Sen Y. Endothelial dysfunction: The link between homocysteine and hydrogen sulfide. Current Medicinal Chemistry. 2014;21(32):3662-3672
  5. 5. Lai WK, Kan MY. Homocysteine-induced endothelial dysfunction. Annals of Nutrition & Metabolism. 2015;67(1):1-12
  6. 6. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation. Clinical and Experimental Immunology. 2007;147(2):227-235
  7. 7. Shastry S, James LR. Homocysteine-induced macrophage inflammatory protein-2 production by glomerular mesangial cells is mediated by PI3 kinase and p38 MAPK. Journal of Inflammation. 2009;6:27. DOI: 10.1186/1476-9255-6-27
  8. 8. Zhang X, Chen S, Li L, Wang Q, Le W. Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1G93A transgenic mice. Europharmacology. 2008;54(7):1112-1119
  9. 9. Wang R, Wang I, Mu N, Lou X, Li W, Chen Y, et al. Activation of NLRP3 inflammasomes contributes to hyperhomocysteinemia-aggravated inflammation and atherosclerosis in apoE-deficient mice. Laboratory Investigation. 2017;97(8):922-934
  10. 10. Filip C, Albu E, Lupascu D, Filip N. The influence of a new rutin derivative in an experimental model of induced hyperhomocysteinemia in rats. Farmacia. 2017;65(4):596-599
  11. 11. Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: Cardiovascular risk factors, therapy, and outcome. Vascular Health and Risk Management. 2005;1(3):183-198
  12. 12. Candido R, Zanetti M, Current p. Diabetic vascular disease: From endothelial dysfunction to atherosclerosis. Italian Heart Journal. 2005;6(9):703-720
  13. 13. Saposnik G, Ray JG, Sheridan P, McQeen M, Lonn E. Homocysteine-lowering therapy and stroke risk, severity and disability: Additional findings from HOPE 2 trial. Stroke. 2009;40(4):1365-1372
  14. 14. Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary disease: A systematic review and meta-analysis. Mayo Clinic Proceedings. 2008 Nov;83(11):1203-1212
  15. 15. Melichar B, Kalabova H, Krcmova L, et al. Serum homocysteine, cholesterol, alpha-tocopherol, glycosylated hemoglobin and inflammatory response during therapy with bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin. Anticancer Research. 2009;29(11):4813-4820
  16. 16. Shukla N, Angelini GD, Jeremy JY. The administration of folic acid reduces intravascular oxidative stress in diabetic rabbits. Metabolism. 2008;57(6):774-781
  17. 17. Terzic–Avdagic. Correlation of coronary disease in patients with diabetes mellitus type 2. Journal of Medical Archives. 2009;63(4):191-193
  18. 18. Snoki K, Iwase M, Sasaki N, Ohdo S, Higuchi S, Matsuyama N, et al. Relations of lysophosphatidylcholine in low-density lipoprotein with serum lipoprotein-associated phospholipase A2, paraoxonase and homocysteine thiolactonase activities in patients with type 2 diabetes mellitus. Diabetes Research and Clinical Practice. 2009;86(2):117-123
  19. 19. Sen U, Rodriguez WE, Tyagi N, Kumar M, Kundu S, Tyagi SC. Ciglitazone a PPAR γ agonist, ameliorate diabetic nephropathy in part through homocysteine clearance. American Journal of Physiology. Endocrinology and Metabolism. 2008;295:E1205-E1212
  20. 20. Wei J, Qiang Y, Yong-ping L, Hui-ming W, Xiang-qun H, Shu-qioa Y, et al. Serum metrix metalloproteinase-9 combined with homocysteine, IL-6, TNF-α, CRP, HbA1c and lipid profile in the incipient diabetic nephropathy with or without macrovascular diseases. Journal of Medical Colleges of PLA. 2007;22(2):111-114
  21. 21. Friedman AN, Hunsicker LG, Selhub J, Bostom AG. Total plasma homocysteine and arteriosclerotic outcomes in type 2 diabetes with nephropathy. Journal of the American Society of Nephrology. 2005;16:3397-3402
  22. 22. Sudha Seshadri MD, Philip A, Wolf MD, Beiser AS, Selhub J, Au R, et al. Association of plasma total homocysteine levels with subclinical brain injury. Archives of Neurology. 2008;65(5):642-649
  23. 23. Vidal J-S, Dufouil C, Ducros V, Tzourio C. Homocysteine, folate and cognition in a large community-based sample of elderly people–The 3C Dijon study. Neuroepidemiology. 2008;30:207-214
  24. 24. Zylberstein DE, Skoog I, Björkelund C, Guo X, Hultén B, Andreasson L-A, et al. Homocysteine levels and lacunar brain infarcts in elderly women: The prospective population study of women in Gothenburg. Journal of the American Geriatrics Society. 2008;56(6):1087-1091
  25. 25. David Smith A, Refsum H, Bottiglieri T, Fenech M, Hoosmand B, McCaddon A, et al. Homocysteine and dementia: An international consensus statement. Journal of Alzheimer's Disease. 2018;62(2):561-570
  26. 26. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: A randomized controlled trial. JAMA. 2005;293(9):1082-1088
  27. 27. Rhew EY, Lee C, Eksarko P, Dyer AR, Tily H, Spies S, et al. Homocysteine, bone mineral density, and fracture risk over 2 years of followup in women with and without systemic lupus erythematosus. The Journal of Rheumatology. 2008;35(2):230-236
  28. 28. Green TJ, McMahon JA, Skeaff CM, Williams SM, Whiting SJ. Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in old persons: A 2-y randomized controlled trial. The American Journal of Clinical Nutrition. 2007;85:460-464
  29. 29. Cagnacci A. Relation of folates, vitamin B12 and homocysteine to vertebral bone mineral density change in postmenopausal women. A five-year longitudinal evaluation. Bone. 42(2):314-320
  30. 30. Filip A, Filip N, Veliceasa B, Filip C, Alexa O. The relationship between homocysteine and fragility fractures–A systematic review. Annual Research & Review in Biology. 16(5). ISSN: 2347-565X
  31. 31. Filip N, Cojocaru E, Filip A, Veliceasa B, Alexa O. Reactive Oxygen Species (ROS) in living cells. In: InTech, editor. Chapter 4 Reactive Oxygen Species and Bone Fragility. Rijeka, Croatia: InTech; 2018. pp. 49-67
  32. 32. Nelen WL, Steegers EA, Eskes TK, et al. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet. 1997;350:861
  33. 33. Merviel P, Cabry R, Lourdel E, Lanta S, Amant C, Copin H, et al. Comparison of two preventive treatments for patient with recurrent miscarriages carrying C677T methylenetetrahydrofolate reductase mutation: 5-year experience. Journal of International Medical Research. 2017;45(6):1720-1730
  34. 34. Abdelsalam T, Karkour T, Elbordiny M, Shalaby D, Abouzeid ZS. Thrombophilia gene mutations in relation to recurrent miscarriage. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2018;7:796-800
  35. 35. Baszczuk A, Kopczynski Z. Hyperhomocysteinemia in patients with cardiovascular disease. Postȩpy Higieny i Medycyny Doświadczalnej. 2014;68:579
  36. 36. Thambyrajah J, Townend JN. Homocysteine and atherothrombosis-mechanism for injury. European Heart Journal. 2000;21:967-974
  37. 37. Upchurch GR Jr, Welch GN, Loscalzo J. Homocysteine, EDRF, and endothelial function. The Journal of Nutrition. 1996;126(4 Suppl):1290S-4S.29
  38. 38. Upchurch GR, Welch G, Fabian A, et al. Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. The Journal of Biological Chemistry. 1997;272:17012-17017
  39. 39. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. The New England Journal of Medicine. 1998;338:1042-1050
  40. 40. Zakrzewicz D, Eickelberg O. From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulmonary Medicine. 2009;9:5
  41. 41. Sydow K, Schwedhelm E, Arakawa N, Bode-Boger SM, Tsikas D, Hornig B, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocysteinemia: Effects of L-arginine and B vitamins. Cardiovascular Research. 2003;57:244-252
  42. 42. Cristiana F, Nina Z, Elena A. Blood cell–An overview of studies in hematology, In: InTech, editor. Homocysteine in Red Blood Cells Metabolism–Pharmacological Approaches. Rijeka, Croatia: InTech; 2012. pp. 31-68. ISBN 978-953-51-0753-8
  43. 43. Ma Y, Peng D, Liu C, Huang C, Luo J. Serum high concentration of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery disease. BMC Cardiovascular Disorders. 2017;17:37
  44. 44. Leoncini G, Bruzzesse D, Signorello MG. Activation of p38 MAPKinase/cPLA2 pathway in homocysteine-treated platelets. Journal of Thrombosis and Hemostasis. 2005;4(1):209-216
  45. 45. Hynynen MM, Khalil RA. The vascular endothelin system in hypertension-recent patents and discoveries. Recent Patents on Cardiovascular Drug Discovery. 2006;1(1):95-108
  46. 46. Chen Y, Liu H, Wang X, Zhang H, Liu E, Su X. Homocysteine up-regulates endothelin type A receptor in vascular smooth muscle cell through SIRT1/ERK1/2 signaling pathway. Microvascular Research. 2017;114:34-40
  47. 47. Demuth K, Atger VÂ, Borderie D, Benoit M-O, Sauvaget D, Lotersztajn S, et al. Homocysteine decreases endothelin-1 production by cultured human endothelial cells. European Journal of Biochemistry. 1999;263:367-376
  48. 48. Salaets K, Schliessman J, Speiser R, Tran A-M, Wang E, Angerio DA. The role of endothelin-1 in atherosclerosis. Georgetown University Journal of Health Sciences. 2006;3(1). https://blogs.commons.georgetown.edu/journal-of-health-sciences/issues-2/previous-volumes/vol-3-no-1-march-2006/role-of-endothelin-1-in-atherosclerosis/
  49. 49. Mangge H, Becker K, Fuchs D, Gostner JM. Antioxidants, inflammation and cardiovascular disease. World Journal of Cardiology. 2014;6(6):462-477
  50. 50. Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L, et al. Homocysteine induces the expression of C–reactive protein via NMDAr-ROS-MAPK-NF-κB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 2014;236:73-81
  51. 51. Xie R, Jia D, Gao C, Zhou J, Sui H, Wei X, et al. Homocysteine induces procoagulant activity of red blood cells via phosphatidylserine exposure and microparticles generation. Amino Acids. 2014;46:1997-2004. DOI: 10.1007/s00726-014-1755-6
  52. 52. Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, Strongin RM. Homocystamides promote free-radical and oxidative damage to proteins. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(2):551-554
  53. 53. Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxidants & Redox Signaling. 2007;9:1941-1958
  54. 54. Zou CG, Banerjee R. Homocysteine and redox signaling. Antioxidants & Redox Signaling. 2005;7:547-559
  55. 55. Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L, et al. Homocysteine induces the expression of C–reactive protein via NMDAr-ROS-MAPK-NF-κB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 2014;236:73-816
  56. 56. Starkebaum G, Harlan JM. Endothelial injury due to cooper-catalyzed hydrogen peroxide generation from homocysteine. The Journal of Clinical Investigation. 1986;77:1370-1376
  57. 57. Filip C, Albu E, Zamosteanu N, Jerca L, Gheorghita N, Jaba IM, et al. Investigarea parametrilor stresului oxidativ in hiperhomocisteinemia provocata experimental la sobolan. Medicina Moderna. 2009;XVI(Suppl. 1):191-193
  58. 58. Albu E, Filip C, Zamosteanu N, Jaba IM, Gheorghita N, Jerca L, et al. The influence on the experimental stress on the plasma level of homocysteine, in rat, therapeutics. Pharmacology and Clinical Toxicology. 2009;XIII(2):143-146
  59. 59. Albu E, Filip C, Zamosteanu N, Dimitriu DC, Jaba IM, Gheorghita N, et al. Investigation of correlation stress-hyperhomocysteinemia. Therapeutics, Pharmacology and Clinical Toxicology. 2009;XIII(3):261-265
  60. 60. Filip C, Albu E, Nina Zamosteanu M, Irina J, Silion M. Hyperhomocysteinemia’s effect on antioxidant capacity on rats. Central European Journal of Medicine. 2010;5(5):620-626
  61. 61. Albu E, Filip C, Zamosteanu N, Jaba IM, Linic IS, Sosa I. Hyperhomocysteinemia is an indicator of oxidant stress. Medical Hypotheses. 2012;78(4):554-555
  62. 62. Stitzinger M. Lipids, inflammation and atherosclerosis, (2007), the digital repository of Leiden University, pdf, Hansson GK inflammation, atherosclerosis and coronary disease. The New England Journal of Medicine. (2005);352:0685-1695
  63. 63. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111:3481-3488
  64. 64. Luis AJ. Atherosclerosis. Nature. 2000;407:233-241
  65. 65. El Oudi M, Aouni Z, Mazigh C, Gazoueni E, Haouela H, Machghoul S. Homocysteine and markers of inflammation in acute coronary syndrome. Experimental and Clinical Cardiology. 2010;15(2):e25-e28
  66. 66. Gori AM, Sofi F, Marcucci R, Abbate R. Association between homocysteine, vitamin B6 concentrations and inflammation. Clinical Chemistry and Laboratory Medicine. 2007;45(12):1728-1736
  67. 67. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutrition Journal. 2015;14:6
  68. 68. Li T, Chen Y, Li J, Yang X, Zhang H, Qin X, Hu Y, Mo Z. Serum homocysteine concentration is significantly associated with inflammatory/immune factors. PLoS One. 2015;10(9)
  69. 69. Xi H, Zhang Y, Xu Y, Yang WY, Jiang SX, Cheng X, et al. Caspase-1 inflammasome activation mediates homocysteine induced pyro-apoptosis in endothelial cells. Circulation Research. 2016;118(10):1526-1539
  70. 70. Carmel R, Jacobsen DW. Homocysteine in Health and Disease. Cambridge University Press; 2001. ISBN: 0 521 65319 3
  71. 71. Harpel PC, Zhang X. Borth, homocysteine and hemostasis: Pathogenic mechanism predisposing to thrombosis. Nutrition. 1996;126(4 Suppl):1285S-1289S
  72. 72. Lentzt SR, Evan Sadler J. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. The Journal of Clinical Investigation. 1991;88:1906-1914
  73. 73. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxidants & Redox Signaling. 2014;20(7):1126-1167
  74. 74. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Current Biology. 2014;24(10):R453-R462
  75. 75. Forman HJ, Maiorino M, Ursini F. Signaling function of reactive oxygen species. Biochemistry. 2010;49(5):835-842
  76. 76. Murphy MP. Mitochondrial thiols in antioxidant protection and redox signaling: Distinct roles for glutathionylation and other thiol modifications. Antioxidants & Redox Signaling. 2012;16:476-495
  77. 77. Forman HJ, Maiorino M, Ursini F. Signaling function of reactive oxygen species. Biochemistry. 2010;49(5):835-842
  78. 78. Czech MP. Differential effects of sulfhydryl reagents on activation and deactivation of the fat cell hexose transport system. The Journal of Biological Chemistry. 1976;251:1164-1170
  79. 79. Mukherjee SP, Lane RH, Lynn WS. Endogenous hydrogen peroxide and peroxidative metabolism in adipocytes in response to insulin and sulfhydryl reagents. Biochemical Pharmacology. 1978;27:2589-2594
  80. 80. Mukherjee SP, Mukherjee C. Similar activities of nerve growth factor and its homologue proinsulin in intracellular hydrogen peroxide production and metabolism in adipocytes. Trans-membrane signaling relative to insulin-mimicking cellular effects. Biochemical Pharmacology. 1982;31:3163-3172
  81. 81. Bahorun T, Soobratte MA, Luximon-Ramma V, Aruoma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update. 2006;1(2):25-41
  82. 82. Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis & Tissue Repair. 2008;1:58
  83. 83. Martindale JL, Holbrook NJ. Cellular response to oxidative stress: Signaling for suicide and survival. Journal of Cellular Physiology. 2002;192(1):1-15
  84. 84. Powers SK, Duarte J, Kavazis AN, Talbert EE. Reactive oxygen species are signaling molecules for skeletal muscle adaptation. Experimental Physiology. 2010;95:1-9
  85. 85. Sun JP, Zhang ZY, Wang WQ. An overview of the protein tyrosine phosphatase superfamily. Current Topics in Medicinal Chemistry. 2003;3(7):739-748
  86. 86. Winterbourn CC, Hampton MB. Thiol chemistry and specificity in redox signaling. Free Radical Biology & Medicine. 2008;45:549-561
  87. 87. Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, et al. The tyrosine phosphatase STEP: Implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry. 2012;2(7):e137
  88. 88. Finkel T. Signal transduction by reactive oxygen species. The Journal of Cell Biology. 2011;194(1):7-15
  89. 89. Louro RO, Diaz-Moreno I. Redox Proteins in Super Complexes and Signalosomes. Boca Raton, FL: CRC Press; 2016. p. 338
  90. 90. Kobayashi Y, Ito K, Kanda A, Tomoda K, Miller-Larsson A, Barnes PJ, et al. Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity. Respiratory Research. 2016;17:30
  91. 91. Marino SM, Gladyshev VN, Marino SM, Gladyshev VN. Cysteine function governs its conservation and degeneration and restricts its utilization on protein surface. Journal of Molecular Biology. 2010;404:902-916
  92. 92. Rhee S. Cell signaling. H2O2, a necessary evil for cell signaling. Science. 2006;312:1882-1883
  93. 93. Brattström L, Wilcken DEL. Homocysteine and cardiovascular disease: Cause or effect? The American Journal of Clinical Nutrition. 2000;72(2):315-323

Written By

Cristiana Filip, Elena Albu, Hurjui Ion, Catalina Filip, Cuciureanu Magda, Radu Florin Popa, Demetra Gabriela Socolov, Ovidiu Alexa and Alexandru Filip

Submitted: 15 September 2018 Reviewed: 02 October 2018 Published: 05 November 2018

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 4 How Homocysteine Modulates the Function of Osteobl...

By Viji Vijayan and Sarika Gupta

1092 downloads

Chapter 1 Introductory Chapter: General Aspects Regarding Ho...

By Nina Filip and Cristina-Elena Iancu

1113 downloads

Chapter 2 HPLC Analysis of Homocysteine and Related Compound...

By Mitsuhiro Wada, Shinichi Nakamura and Kenichiro Na...

1493 downloads