A cardioprotective insight of the cystathionine γ-lyase/hydrogen sulfide pathway

Abstract

Traditionally, hydrogen sulfide (H₂S) was simply considered as a toxic and foul smelling gas, but recently H₂S been brought into the spot light of cardiovascular research and development. Since the 1990s, H₂S has been mounting evidence of physiological properties such as immune modification, vascular relaxation, attenuation of oxidative stress, inflammatory mitigation, and angiogenesis. H₂S has since been recognized as the third physiological gaseous signaling molecule, along with CO and NO [65,66]. H₂S is produced endogenously through several key enzymes, including cystathionine β-lyase (CBE), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)/cysteine aminotransferase (CAT). These specific enzymes are expressed accordingly in various organ systems and CSE is the predominant H₂S-producing enzyme in the cardiovascular system. The cystathionine γ-lyase (CSE)/H₂S pathway has demonstrated various cardioprotective effects, including anti-atherosclerosis, anti-hypertension, pro-angiogenesis, and attenuation of myocardial ischemia-reperfusion injury. CSE exhibits its anti-atherosclerotic effect through 3 mechanisms, namely reduction of chemotactic factor inter cellular adhesion molecule-1 (ICAM-1) and CX3CR1, inhibition of macrophage lipid uptake, and induction of smooth muscle cell apoptosis via MAPK pathway. The CSE/H₂S pathway's anti-hypertensive properties are demonstrated via aortic vasodilation through several mechanisms, including the direct stimulation of K_ATP channels of vascular smooth muscle cells (VSMCs), induction of MAPK pathway, and reduction of homocysteine buildup. Also, CSE/H₂S pathway plays an important role in angiogenesis, particularly in increased endothelial cell growth and migration, and in increased vascular network length. In myocardial ischemia-reperfusion injuries, CSE/H₂S pathway has shown a clear cardioprotective effect by preserving mitochondria function, increasing antioxidant production, and decreasing infarction injury size. However, CSE/H₂S pathway's role in inflammation mitigation is still clouded, due to both pro and anti-inflammatory results presented in the literature, depending on the concentration and form of H₂S used in specific experiment models.

Keywords: Akt, protein kinase B; Angiogenesis; Atherosclerosis; BCA, brachiocephalic artery; CAM, chorioallantoic membrane; CAT, cysteine aminotransferase; CBS, cystathionine β-lyase; CLP, cecal ligation and puncture; CSE KO, CSE knock out; CSE, cystathionine γ-lyase; CTO, chronic total occlusion; CX3CL1, chemokine (C-X3-C Motif) ligand 1; CX3CR1, CX3C chemokine receptor 1; Cystathionine γ-lyase; EC, endothelial cell; ERK, extracellular signal-regulated kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSH-Px, glutathione peroxidase; GYY4137, morpholin-4-Ium-4-methoxyphenyl(morpholino) phosphinodithioate; H2S, hydrogen sulfide; HUVECs, human umbilical vein endothelial cells; Hydrogen sulfide; ICAM-1, inter cellular adhesion molecule-1; IMT, intima–media complex thickness; Ischemia–reperfusion injury; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MPO, myeloperoxidase; MST, 3-mercaptopyruvate sulfurtransferase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; PAG, DL-propagylglycine; PPAR-γ, peroxisome proliferator-activated receptor; PTPN1, protein tyrosine phosphatase, non-receptor type 1; ROS, reactive oxygen species; S-diclofenac, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-Yl)-phenyl ester; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SMCs, smooth muscle cells; SOD, superoxide dismutase; VEGF, vascular endothelial growth factor; VSMCs, vascular smooth muscle cells; Vasorelaxation; l-NAME, NG-nitro-l-arginine methyl ester; oxLDL, oxidized low density lipoprotein.

Fig. 1

Diagram of the transsulfuration pathway. The majority of endogenous H₂S is produced through the transsulfuration pathway, which utilizes methionine-derived l-cysteine as substrate for CSE and CBE enzymes to form H₂S. An alternative route exists where l-cysteine is first converted to 3-mercaptopyruvate before reacting with MST enzyme to form H₂S. MST = mercaptopyruvatesulfurtransferase, CAT = cysteine aminotransferase, GNMT = glycine N-methyltransferase, GSS = Glutathione synthase, CSAD = cysteine sulfinic acid decarboxylase.

Fig. 2

H₂S function in atherosclerosis. The precipitating factors of atherosclerosis include endothelial damage, vascular inflammation, and smooth muscle proliferation. H₂S functions to attenuate leukocyte chemotaxis through down regulation of ICAM-1 and CX3CR1/CX3CL1. Moreover, H₂S inhibits foam cell formation through down regulating CD36, SR-A, and ACAT-1 surface markers and decreases oxLDL uptake in macrophage. Further, H₂S induces vascular smooth muscle apoptosis through up regulating ERK 1/2 and p21^Cip/WAF-1 and by down regulating cyclin D1.