Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries

Review Article

J Cardiovasc Disord. 2021; 7(2): 1046.

Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries

Cacciapuoti F*

Department of Internal Medicine, “Luigi Vanvitelli”-Campania-University, Italy

*Corresponding author: Federico Cacciapuoti, Department of Internal Medicine, “Luigi Vanvitelli” Campania University, Piazza L. Miraglia, 2 Naples, Italy

Received: July 02, 2021; Accepted:July 30, 2021; Published: August 06, 2021

Abstract

Increased Homocysteine Levels (HHcy) is an independent risk factor for atherosclerosis. On the other hand, hydrogen sulfide (H2S) exerts a protection against cardiovascular injuries. On the contrary, accumulating evidences showed that downregulation of defective catabolism of HHcy, with reduced H2S synthesis, is involved in the pathogenesis of a variety of cardiovascular diseases. In that occurrence, the detrimental actions on cardiovascular structures performed by HHcy are added to the negative consequences of reduced H2S (in part unlike each HHcy) on cardiovascular system. Therefore, when the reduced re-methylation pathway of Hcy towards Met (resulting in HHcy) is contemporarily added to the decreased trans-sulfuration pathway (inducing a reduction of H2S synthesis) cardiovascular impairment significantly increases.

Keywords: Homocysteine; Hydrodgen sulfide; Re-methylation pathway; Trans-sulfuration pathway; Endothelial dysfunction; Cardiovascular injuries

Abbreviations

Hcy: Homocysteine; Met: Methionine; MTHFR: Methylene- Tetra-Hydrofolate Reductase; MS: Methionine; Synthase; GHS”: Glutathione; MAT: Methionine-Adenosyl-Transferase; SAM: S-Adenosyl-Methionine; SAH: S-Adenosyl-Homocysteine; DNA: Desossi-Nucleic Acid; RNA: Ribo-Nucleic Acid; DMG: Di-Methyl- Glycine; CΒS: Cystationine-Β-Synthase; CSE: Cystationine-Gamma- Lyase; 3-MST: 3-Mercaptopyruvate-Sulfur-Transferase; H2S: Hydrogen Sulfide; HHcy: HyperHomocysteine; ED: Endothelial Dysfunction; Ecs: Endothelial Cells; NO: Nitric Oxide; DDAH: Dimethylarginine-Dimethyl-Amino Hydrolase; NOS: Nitric Oxide Synthase; ROS: Reactive Oxygen Species; ONOO: Peroxynitrite; TxA2: Tromboxane A2; ADP: Adenosyl-D-Phosphate; OH: Hydroxyl Radical; H2O2: Hydrogen Peroxide; cAMP: cyclic Adenosine-Mono- Phosphate; VSMC: Vascular Smooth Muscle Cell; ATP: Adenosin- Tri-Phosphate; VCAM: Adhesion Molecule; MCP-1: Monocyte Chemoattractant Protein-1; NF-kB: Nuclear Factor kB; CAM-1: Adhesion Molecule-1; NaHS: Sodium Hydrosulfide; I/R: Ischemia/ Reperfusion

Introduction

Homocysteine (Hcy) is a sulfur-containing amino acid derived, as metabolite, by a dietary Methionine (Met). That is present in several aliments, such as meat, fish and dietary products. Further meta bolization of Hcy happens by two means: remethylation to Met and trans-sulfuration to Cysteine and Glutathione (GSH) [1,2]. The former involves the enzymes MethyleneTetra-Hydro-Folate Reductase (MTHFR) and Methionine Synthase (MS). In this pathway, Met is subsequently activated in S-Adenosyl-Methionine (SAM) by Methionine Adenosyl-Transferase (MAT). SAM acts as a methyl donor (-CH3) to some substrates, such as DNA, neurotransmitters, RNA, proteins, amino acids, phospholipids, monoamines, and others by a process of trans-methylation [3,4]. Subsequently, SAM is changed in S-Adenosyl-Homocysteine (SAH). A second route of Hcy re-methylation in not-dependent on folate and requires Betaine as 1C donor (Betaine cycle). The reaction results in the production of Dimethylglycine (DMG) and happens in the liver and kidney alone. Further Hcy-catabolization happens via transsulfuration pathway (Figure 1). In this route, Hcy is converted in Cystathionine by the enzyme Cystathionine-Β-Synthase (CBS). That is acted by the enzyme Cystathionine-gamma-Lyase (CSE) to generate Cysteine. In turn Cysteine, through the enzyme 3-Mercaptopyruvate Sulfur- Transferase (3-MST), produces a gaseous and malodorous mediator toxic gas called Hydrogen Sulfide (H2S). From the gas drives the powerful antioxidant GHS [5]. Among three enzymes involved in transsulfuration pathway, CBS and CSE participate in the interconversion of Hcy in Cysteine. The steps of transsulfuration pathway until the H2S synthesis are schematized in Figure 2. The majority of studies in this pathway was performed on animals and has focused for CSE [6]. It must be added that, when dietary Met intake is low prevails the remethylation pathway; on the contrary, when Met intake is high prevails the trans-sulfuration pathway.

Figure 1: Re-methylation, Trans-methylation and Trans-sulfuration pathways of the homocysteine2 cycle are and hy.

    

    
    

    

    Figure 1: Re-methylation, Trans-methylation and Trans-sulfuration pathways of the homocysteine2 cycle are and hy.

Figure 2: Catabolism of homocysteine through transsulfuration pathway, with hydrogen sulfide (H2S) synthesis, is reported in detail.

    

    
    

    

    Figure 2: Catabolism of homocysteine through transsulfuration pathway, with hydrogen sulfide (H2S) synthesis, is reported in detail.

Normal level of Hcy is less than 15μmo/L. An increased Hcy levels (HHcy) can happen for genetic defects of the enzymes (MTHFR, MS, MAT) and/or folic acid or B12 vitamin (in the re-methylation pathway), or the enzymes (CBS, CSE, 3-MST) and/or B6 (in the transsulfuration pathway).

HHcy may derive from genetic factors, such as polymorphisms of the enzymes involved in Hcy metabolism or a dietary deficiencies of vitamin B6, riboflavin, cobalamin and/or folate. The genetic polymorphisms of the enzymes inducing HHcy include: CBS, MTHFR, MS. Polymorphisms of MTHFR or MS give rise to low or normal level of plasma MET, while deficiency of CBS lead to HHcy. The further Cystationine catabolism towards Cysteine requires the enzyme CSE, whereas the enzyme 3-MST induces H2S synthesis from L-Cysteine [7].

It is known that HHcy is associated with atherosclerosis and its some frequent complications, such as myocardial infarction and stroke or peripheral vascular disease [8]. But, HHcy also favors some neurological disorders, such as dementia, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, epilepsy, eclampsia and others [9]. HHcy can cause cardiovascular disease not only “per se” [10] but also, through the deficiency of H2S [11]. On the subject, the detrimental effects on CV system induced by HHcy are the same caused by H2S deficiency, and few others only are dependent from H2S (Figure 3). H2S is a gaseous and malodorus mediator endogenously produced from Cysteine (transsulfuration pathway). A number of studies demonstrated that H2S deficiency may be involved in a multitude of pathophysiologic processes, such as impaired vascular tone, oxidative stress, inflammation and atherosclerosis [12,13].

Figure 3: Main effects on CV system of both HHcy and low H2S. Different effects performed by two conditions are underlined.

    

    
    

    

    Figure 3: Main effects on CV system of both HHcy and low H2S. Different effects performed by two conditions are underlined.

Increase of Hcy/H2S Ratio

HHcy state causes a decrease in H2S production because it inhibits CSE activity [12]. Concordandly, deficiency of H2S was found in hyperhomocysteinemic mice [14]. A reduction of H2S tissue concentration was also observed in cells exposed to HHcy [15-17]. The decrease of H2S was attribuited to suppressed H2S synthesis generating enzymes CBS and CSE. CBS expression predominates in the brain, nervous system, liver and kidneys, while CSE is a major H2S-sintetizing enzyme present in cardiovascular system [18]. Contrarily to these reports, few studies report elevated H2S levels in HHcy [19,20]. But, the mechanisms of this anomalous behaviour (increase of H2S in presence of HHcy) remain unknown.

As previously said, H2S deficiency is caused by the reduced activity/ expression of the enzymes, as CBS, CSE induced by HHcy [21]. H2S deficiency, derived by reduced activity of these enzymes, acts as the risk factor for cardiovascular disorders [22-25]. Therefore, both HHcy and H2S deficiency induce cardiovascular disease and the increased HHcy/H2S ratio, (for raised Hcy concentration and reduced H2S production) is as a more heavy indicator of cardiovascular injuries. Endothelial Dysfunction (ED) is a prevalent mechanism by which both conditions and its ratio causes cardio-vascular impairment [26] but, other mechanisms happen too.

Endothelium

The health endothelium is a dynamic organ that regulates vascular tone by balancing vasodilation and vasoconstriction in response to different stimuli. Endothelial Cells (ECs) constitutes a mechanical and biological barrier located between the vessels and tissues, and regulates the exchanges between the interstitial tissue and blood. Endothelium is exposed to shear stress due to the blood flow, that may alter its permeability. So, normal endothelium plays a critical role in cardiovascular homeostasis, by regulating the blood fluidity, coagulation and fibrinolysis, angiogenesis, vascular tone, monocyte/leukocyte adhesion. Specifically, Ecs produce some vasoactive substances to maintain vascular tone. Furgott and Zawadzki firstly described the presence in Ecs of substances inducing vasodilatation, such as Nitric Oxide (NO) and endothelium-derived hyperpolarizing factor and prostacyclin [27]. Other substances favoring vasoconstriction, such as endothelin and thromboxane, were present too. The balance between these two groups of compounds having opposite effects allows to maintain the vascular tone. It must be added that Ecs produce some molecules able to counteract thrombosis, inflammation and smooth muscle cells proliferation [28- 30].

Endothelial Dysfunction (ED) consists in the disruption of the integrity of Ecs and refers to the loss of their physiological functions caused by HHcy and H2S [31-33].

HHcy and Vascular Injury

HHcy reduces the NO synthesis through the inhibition of Dimethylarginine-Dimethyl-Amino-Hydrolase (DDAH). The compound is involved in the metabolism of Asymmetric-D-Methyl- Arginine (ADMA), an enzyme that inhibits Nitric Oxide Synthase (NOS) [34].

HHcy favors the oxidative stress, inducing the formation of Reactive Oxygen Species (ROS) through the inhibition of the expression and function of some anti-oxidant enzymes, such as superoxide dismutase and glutathione peroxidase [35,36]. The superoxide anion (O-2) interacts with NO forming peroxynitrite (ONOO). On the other hand, the production of ONOO is a cause of the thromboxane formation (TxA2), having an arteriolar vasoconstrictive action.

HHcy increase collagen deposition leading vascular fibrosis. In an animal study, Liu et al. demonstrated that the increase of Hcy concentration favors an increase of connective tissue growth factor in vascular smooth muscle cells involved in atherosclerotic plaque progression [37].

HHcy also favours platelets’ activation by increasing their sensitivity to ADP [38]. The increased Hcy concentration promotes the activation of Factor V Leiden, impairs the von Willebrand factor secretion, inhibits protein the C activation, so promoting the activation of coagulation cascade, favoring the coagulative process [39].

HHcy, favoring oxidative stress, also causes inflammation process [40].

Finally, HHcy acts on the Glutathione (GSH) synthesis, impairing the ratio oxidized/reduced Glutathione (GSSG/GSH) for reduced GSH synthesis, the main antioxidant compound in the body. This reduction happens for decreased activity of the glutathione peroxidase. The prevalence of GSSG on GSH is the expression of greater oxidative stress. Contrarily, the GSH prevalence protects cells by ROS production [41].

H2S Deficiency and Vascular Injury

The role of H2S in the endothelium assumed considerable importance in the last decade. Lower H2S concentration causes vasocontriction. The vasoconstrictive effect of reduced H2S concentration derives from the inactivation of NO (through the NOS inactivation) [42].

H2S deficiency causes oxidative stress. As previous affirmed, this consists in an imbalance between oxidant and antioxidant systems for excessive formation of ROS, as superoxide anion (02-), hydroxyl radical (OH-), peroxynitrite (ONOO-)) and hydrogen peroxide (H2O2). While HHcy directly induces this condition, H2S deficiency indirectly can cause oxidative stress through the GSH depletion [43]. Particularly, in the presence of H2S deficiency, ROS decreases cyclic Adenosine-Monophosphate (cAMP) in vascular smooth muscle VSMC, inducing the vasoconstrictive effect [43].

Presumably H2S performs a twofold, conflicting action on inflammation. At low concentration, it seems to inhibit the inflammation, while at high concentration seems to have a proinflammatory effect through the activation of Adenosine-Tri-Phosphate (ATP)-sensitive K+ channels [44]. But, in other studies, H2S acts a regulator of leukocyte activation under inflammatory states. In accordance with this, endogenous H2S deficiency exacerbates leukocyte-mediated inflammation. On the contrary, its normal concentration reduced leukocytes [45]. It was also affirmed that a reduction of H2S synthesis, for CSE deletion, resulted associate with endothelial inflammation [46]. In addition, H2S deficiency reduces adhesion molecule-1 (VCAM-1) and Monocyte Chemoattractant Protein-1 (MCP-1). Contrarily, exogenous H2S administration attenuates Ang II-induced inflammatory response, via the inhibition of the NF-kB pathway [47].

In addition, the reduced synthesis of H2S plays a pathophysiologic role in the development of atherosclerosis and plaque instability [48,49]. Wang at al. demonstrated that H2S deficiency increased the expression of adhesion molecule-1 (CAM-1) that sustains atherosclerotic process [50].

However, the lack of H2S favors the atherosclerotic process also by increasing the proliferation of intima and smooth muscle cells [51]. Further, a down regulation of CSE expression seems to have a role in the progression of atherosclerosis and plaque calcification [51]. Concerning that, Wu and al. demonstrated in rats that a vascular calcification-model reduces after NaHS (a generator of H2S) administration [52].

H2S deficiency (through CSE reduction) results in decrease of Gluthatione (GSH) biosynthesis [53]. GSH is a tripeptide composed by glutamate, cysteine and glycine. It functions as a powerful cellular antioxidant against oxidative damage caused by ROS. Its deficiency impairs endothelium-dependent vasodilation, increases arterial hypertension, favors pro-inflammatory reaction. Its decreased synthesis induces atherosclerosis, plaques’ formation and rupture [54].

Finally, low H2S favours the heart-injuries depending from ischemia/reperfusion (I/R) through an unspecified mechanisms. I/R may be defined as a condition characterized by a deprivation of blood flow supply followed by the subsequent restoration of reperfusion [55]. It is one of major causes of morbidity and mortality in the world. Injuries of I/R happen in hypertension, atherosclerosis, heart failure and others. The organs involved are: apart from heart, liver, kidney, brain, intestine and others [55]. Several mechanisms are proposed as mediators of the damage induced by I/R, such as activation of complement system, endoplasmic reticulum stress, calcium overload, activation of apoptosis, necrosis, autophagy and others [56].

Conclusions

HHcy is caused by a defective remethylation, for MTHFR or MS genetic polymorphism or folate or vitamin B12 deficiency. An increased Hcy concentration complicates with reduced synthesis of H2S when a decreased trans-sulfuration pathway is contemporarily present. This comes true in the presence of vitamin B6 deficiency or CBS, CSE or MST genetic polymorphism. On the other hand, HHcy has been reported to inhibit CSE activity altering the transsulfuration pathway, thereby reduce endogenous H2S production [13]. Consequently, an increased Hcy/H2S ratio comes, for increase of the numerator and decrease of the denominator. In this condition vascular injuries especially happen, because vascular derangements [10,57] are added to the vascular injuries (due to H2S deficiency) [21,58]. Thus, the Hcy/H2S ratio can be considered as a biomarker able to induce vascular injuries more than HHcy and H2S deficiency esteemed separately. But, further investigations must be performed to definitively verify this acquisition.

References

  1. Selhub J. Homocysteine metabolism. Ann. Review Nutr. 1999; 19: 217-246.
  2. Kumar A, Paifrey HA, Patrak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr. Metabol. 2017; 14: 78.
  3. Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Ped. 1998; 157: S40-S44.
  4. Gao J, Cahil CM, Huang X, Roffman JL, Lamon-Fava S, Fava M. et al. S-Adenosyl-Methionine and transmethylation pathways in neuropsychiatric disease throughout life. Neurotherapeutics. 2018; 15: 156-175.
  5. Sbodio JI, Snyder SH, Paul BD.: Regulators of the transsulfuration pathway. Br J Pharmacol. 2019; 176: 583-593.
  6. Beard RS, Bearden SE. Vascular complications of cystationine-beta-synthase deficiency: future complications of cystationine-beta-synthase deficiency: future directions for homocysteine-to hydrogen sulfide research. Am J Physiol Heart Circ Physiol. 2011; 300: H13-H26.
  7. Mattews RG, Elmore CL. Defects in homocysteine metabolism: diversity among hyperhomocysteinemias. Clin. Chem. Lab. Med. 2007; 45: 1700- 1703.
  8. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: control of aging: a meta-analysis. JAMA. 2002; 288: 2015-2022.
  9. Ansari R, Malleck E, Luo JJ. Hyperhomocysteinemia and neurological disorders: a review. J Clin Neurol. 2014; 10: 281-288.
  10. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutrition Journ. 2015.
  11. Gorini F, Bustaffa E, Chatzinognostu K, Bianchi F. Vassalle C. Hydrogen sulfide and cardiovascular disease: doubts, clues, and interpretation difficulties from studies in geothermal areas. Sci. Total Environ. 2020; 743.
  12. Yang Q, He GW. Imbalance of homocysteine and H2S: significance, metabolisms, and therapeutic promise in vascular injury. Ox Med Cell Longevity. 2019.
  13. Li JJ, Li Q, Du HP, et al. Homocysteine triggers inflammatory response in macrophages through inhibiting ncse-h2s signaling via DNA hypermethylation of cse promoter. Inter J Med Sci. 2015; 16: 12560-12577.
  14. Li MH, Tang JP, Zhang P, et al. Disturbance of endogenous hydrogen sulfide generation and endoplasmic reticulum stress un hippocampus are involved in homocysteine-induced defect in learning and memory of rats. Behav. Brain Res. 2014; 262: 35-41.
  15. Tang XQ, Sen XT, Huang YE, et al. Inhibition of hydrogen disulfide generation is associated with homocysteine-induced neurotoxicity. Role of erk1/2 activation. J Mol Neurosci. 2011; 45: 60-67.
  16. Nakano S, Ishii I, Shimura K, et al. Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions. Journ Mol. Med. 2015; 93: 879-889.
  17. Yang G, Wang R. H2S and blood vessels: an overview. Handb Exp Pharmacol. 2015; 230: 85-110.
  18. d’Emmanuele di Villa Bianca R, Mitidieri MND, Di Minno G, et al. Hydrogen sulfide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia. Proc Natl Acad Sci. 2013; 110: 15812-15817.
  19. Cui X, Navneet S, Wang J, et al.: Analysis of mthfr, cbs, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice. Invest Ophtal Visual Sci. 2017; 58: 1954-1963.
  20. Pan LL, Liu XH, Gang QH, Yang HB, Zhu YZ. Role of Cystationinegamma- lyase/Hydrogen Sulfide pathway in cardiovascular disease: a novel therapeutic strategy. Antioxid. Redox Signal 2012; 17: 106-118.
  21. Mani S, Li H, Untereiner A, Wu L, Yang G, Austin RC, et al. Decreased endogeneous production of hydrogen sulfide accelerates atherosclerosis. Circulation. 2013; 127: 2523-2534.
  22. Kondo K, Bhushsan S, King AL, Prablu SD, Hamid T, Koenig S, et al. H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013; 127: 1116-1127.
  23. Shen Y, Shen Z, Luo S, Guo W, Zhu YZ. The cardioprotective effects of hydrogen sulfide un heart diseases: from molecular mechanisms to therapeutic potential. Ox Med Cell. Longevity. 2015.
  24. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence or causality from a meta-analysis. BMJ. 2002; 325: 1202.
  25. Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine, and cardiovascular disease: judging casuality in the face of inconclusive trial evidence. BMJ. 2006; 333: 1114-1117.
  26. Kruger-Cange A, Bloki A, Franke RP, Jung F. Vascular cell biology: an update. Int J Mol Sci. 2019.
  27. Fuchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288: 373-376.
  28. Lerman A, Burnett JC. Intact and altered endothelium in the regulation of vasomotion. Circulation. 1992; 86: III12-III19.
  29. Rubany GM. The role of endothelin in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol. 1993; 22: S1-S14.
  30. Tyagi SC, Smiley LM, Mujumdar VS. Homocysteine impairs endothelial function. Can. Journ. Physiol. Pharmacol. 1999; 77: 950-957.
  31. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115: 1285-1295.
  32. Cheng Z, Yang X, Wang H. Hyperhomocysteinemia and endothelial dysfunction. Curr Hypert Rev. 2009; 5: 158-165.
  33. Citi V, Martelli A, Gorica E, Brogi S, Testai L, Calderrone V. Role of hydrogen disulfide in endothelial dysfunction: pathophysiology and therapeutic approaches. J Adv Res. 2021; 27: 99-113.
  34. Hoffman M. Hypothesis: hyperhomocysteinemia as an indicator of oxidant stress. Med. Hyp. 2011; 77: 1088-1093.
  35. Loscalzo J. The oxidant stress of hyperhocysteinemia. J Clin Invest. 1996; 98: 5-7.
  36. Weiss N. Mechanisms of increased vascular stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metabol. 2005; 61: 27-36.
  37. Liu X, Luo F, Li J, Wu W, Li L, Chen H. Homocysteine induces connective tissue growth factor expression in vascular smooth muscle cells. J Thromb Hemost. 2008; 6: 184-192.
  38. Riba R, Nicolaou A, Troxler M, Homer-Vaniasiknam S, Naseem RM. Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels. Atherosclerosis 2004; 175: 69-75.
  39. Gendes VE, Hovinga HA, ten Cate H,Macgillary MR, Leijte A, Reitsma PH, et al. Homocysteine and markers of coagulation and endothelial cell activation. J Throm Hemost. 2004; 2: 445-451.
  40. Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antiox Redox Sign. 2007; 9: 1941-1958.
  41. Cacciapuoti F. N-Acetyl-Cysteine supplementation lowers high homocysteine plasma levels and increase Glutathione synthesis in the transsulfuration pathway. Ital Journ Med. 2019; 13: 234-240.
  42. Kubo S, Kurokawa Y, Doe L, Masuko T, Sekiguchi F, Kawabata A. Hydrogen sulfide inhibits activity of three isoforms of recombinant nitric oxide synthase. Toxicology. 2007; 241: 92-97.
  43. Lim JJ, Liu YH, Khin ESW, Bian JS. Vasoconstrictive effect of hydrogen disulfide involves downregulation of cAMP in vascular smooth muscle cells. Am J Physiol Cell Physiol. 2008; 295: C1261-C1270.
  44. Li L, Bhatia M, Zhu YZ, Zhu YC, Ramnath RD, Wang ZJ, et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J. 2005; 19: 1196-1198.
  45. Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL. Hydrogen sulfide is an endogenous modulator of leukocyte-mediate inflammation. FASEB J. 2006; 20: 2118-2120.
  46. Bibli SI, Hu J, Sigala F, Wittig I, Hedler J, Zukunft S, et al. Tionine gamma lyase sulfhydrates the RNA binding protein human antigen to preserve endothelial cell function and delay atherogenesis. Circulation. 2019; 139: 1021-114.
  47. Hu H, Jiang ZS, Zhou SH, Liu Q. Hydrogen sulfide suppresses angiotensin II-stimulated endothelin_1 generation and subsequent cytotoxicity-induced endoplasmic reticulum stress in endothelial cells via NF-kB. Mol Med Rep. 2016; 14: 4729-4740.
  48. Kanagy NL, Szabo C, Papapetropulos A. Vascular biology of hydrogen sulfide. Am J Physiol Cell Physiol. 2017; 312: C537-C549.
  49. Kavurma MM, Rayner HJ, Karunakaran D. The walking dead: macrophage inflammation and death in atherosclerosis. Curr Opin Lipidol. 2017; 28: 91-98.
  50. Wang Y, Zhao X, Jin H, Wei H, Li W, Bu D, et al. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscl. Thromb Vasc Biol. 2009; 29: 173-179.
  51. Qiao W, Chaoshu T, Hongfang J, Junbao D. Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis. Biochem Biophys Res Commun. 2010; 396: 182-186.
  52. Wu SY, Pan CS, Geng B, Zhao J, Yu F, Pang YZ, et al. Hydrogen sulfide ameliorates vascular calcification induced by vitamin D3 plus nicotine in rats. Acta Pharmacol. Sin. 2006; 27: 299-306.
  53. Yang G, Wu L, Jang B, Qi J, Cao K, Meng Q, et al. H2S as a physiologic vasorelaxant: hypertension in mice with depletion of cystationine-gammalyase. Science. 2008; 322: 587-590.
  54. Torzewski M, Ochsenhirt V, Kieschov AL, Oelze M, Dalber A, Li H, et al. Deficiency of Glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscl Thromb Vasc Biol. 1007; 27: 850-857.
  55. Stein A, Baily SM. Redox biology of hydrogen sulfide: implications for physiology, pathophysiology, and pharmacology. Redox Biology. 2013; 1: 32-39.
  56. Wu D, Wang J, Li H, Xue M, Ji A, Li Y, et al. Role of hydrogen sulfide in ischemia-reperfusion injiury. Oxidative Med Cell Longevity 2015.
  57. Fu Y, Wang X, Kong W. Hyperhomocysteinemia and vascular injury: advances in the mechanisms and drug targets. British Journ Pharmacol. 2018; 175: 21173-1189.
  58. Possomato-Vieira VH, Goncalves-Rizzi VH, do Nascimento RA, et al. Clinical and experimental evidences of hydrogen sulfide involvement in lead-induced hypertension. BioMed Res Intern. 2018.

Citation: Cacciapuoti F. Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries. J Cardiovasc Disord. 2021; 7(2): 1046.