Regulation of Cystathionine γ-Lyase Expression in the Cardiovascular System: Insights into Exogenous Hydrogen Sulfide, Hydrogen Peroxide, Hypoxia, and Nuclear Factor kB Signaling
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Abstract
Cystathionine γ-lyase is a key enzyme in the transsulfuration pathway responsible for endogenous hydrogen sulfide production in the cardiovascular system. As the third gaseous signaling molecule, hydrogen sulfide plays crucial roles in maintaining vascular homeostasis, regulating vasodilation, and protecting against ischemia-reperfusion injury. This review comprehensively analyzes the regulatory mechanisms governing cystathionine γ-lyase expression under various physiological and pathological conditions. Exogenous hydrogen sulfide exhibits concentration-dependent bidirectional regulation of cystathionine γ-lyase expression, with lower concentrations (10-80 μM) suppressing cystathionine γ-lyase through feedback inhibition, while higher concentrations (120-160 μM) upregulating its expression as a protective response. Hydrogen peroxide , at moderate concentrations (5 μM), significantly enhances cystathionine γ-lyase promoter activity and mRNA/protein expression, suggesting a potential feedback loop where cystathionine γ-lyase -derived hydrogen sulfide scavenges reactive oxygen species. Hypoxia regulates cystathionine γ-lyase through transcriptional and post-transcriptional mechanisms, with increased cystathionine γ-lyase expression potentially protecting cells by elevating hydrogen sulfide levels and buffering oxygen consumption. Furthermore, lipopolysaccharide-induced cystathionine γ-lyase expression critically depends on the Nuclear Factor κB transcription factor binding site (GGACATTCC) within the cystathionine γ-lyase promoter, establishing a direct link between inflammatory signaling and hydrogen sulfide biosynthesis. Based on these findings, we propose a mechanistic hypothesis wherein hypoxia-induced cardiomyocyte apoptosis releases hydrogen peroxide, which activates Nuclear Factor κB signaling in vascular endothelial cells to upregulate cystathionine γ-lyase expression, leading to enhanced hydrogen sulfide production and subsequent vasodilation. Understanding these regulatory networks provides theoretical foundations for developing therapeutic strategies targeting the cystathionine γ-lyase/hydrogen sulfide pathway in cardiovascular diseases, including myocardial infarction, hypertension, and atherosclerosis.
Keywords: Cystathionine γ-lyase; Hydrogen sulfide; Hypoxia; Nuclear Factor κB; Cardiovascular regulation
Keywords:
Cystathionine gamma-lyase, Hydrogen sulfide, Hypoxia, Nuclear Factor kappaB, Cardiovascular regulation
Article Details
How to Cite
WANG, Maoxian.
Regulation of Cystathionine γ-Lyase Expression in the Cardiovascular System: Insights into Exogenous Hydrogen Sulfide, Hydrogen Peroxide, Hypoxia, and Nuclear Factor kB Signaling.
Medical Research Archives, [S.l.], v. 14, n. 4, may 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7409>. Date accessed: 24 june 2026.
doi: https://doi.org/10.18103/mra.v14i4.7409.
Keywords
Cystathionine ?-lyase; Hydrogen sulfide; Hypoxia; NF-?B; Cardiovascular regulation
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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5. Yang, G., et al. Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells. Cardiovascular research 86, 487-495 (2010).
6. Xu, M., et al. Hydrogen sulfide: Recent progress and perspectives for the treatment of dermatological diseases. J Adv Res 27, 11-17 (2021).
7. Gall, T., et al. Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis. Redox Biol 57, 102504 (2022).
8. Yan, S.K., et al. Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 351, 485-491 (2006).
9. Yang, G., Wu, L. & Wang, R. Pro-apoptotic effect of endogenous H2S on human aorta smooth muscle cells. FASEB J 20, 553-555 (2006).
10. Elrod, J.W., et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci U S A 104, 15560-15565 (2007).
11. Yang, G., et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322, 587-590 (2008).
12. Zhang, J., Xie, Y., Xu, Y., Pan, Y. & Shao, C. Hydrogen sulfide contributes to hypoxia-induced radioresistance on hepatoma cells. J Radiat Res 52, 622-628 (2011).
13. Alshahwan, H., et al. Hydrogen sulfide donor GYY4137 attenuates vascular complications in mesenteric bed of streptozotocin-induced diabetic rats. Eur J Pharmacol 933, 175265 (2022).
14. Beltowski, J. & Kowalczyk-Boltuc, J. Hydrogen sulfide in the experimental models of arterial hypertension. Biochem Pharmacol 208, 115381 (2023).
15. Geng, B., et al. H2S generated by heart in rat and its effects on cardiac function. Biochemical and biophysical research communications 313, 362-368 (2004).
16. Osmond, J.M. & Kanagy, N.L. Modulation of hydrogen sulfide by vascular hypoxia. Hypoxia (Auckl) 2, 117-126 (2014).
17. Pushpakumar, S., Kundu, S. & Sen, U. Endothelial dysfunction: the link between homocysteine and hydrogen sulfide. Curr Med Chem 21, 3662-3672 (2014).
18. Kimura, H. Signaling molecules: hydrogen sulfide and polysulfide. Antioxid Redox Signal 22, 362-376 (2015).
19. Sabino, J.P., Traslavina, G.A. & Branco, L.G. Role of central hydrogen sulfide on ventilatory and cardiovascular responses to hypoxia in spontaneous hypertensive rats. Respir Physiol Neurobiol 231, 21-27 (2016).
20. Leucker, T.M., et al. Cystathionine gamma-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6. Am J Physiol Heart Circ Physiol 312, H711-H720 (2017).
21. Webb, G.D., et al. Contractile and vasorelaxant effects of hydrogen sulfide and its biosynthesis in the human internal mammary artery. J Pharmacol Exp Ther 324, 876-882 (2008).
22. Ariyaratnam, P., Loubani, M. & Morice, A.H. Hydrogen sulphide vasodilates human pulmonary arteries: a possible role in pulmonary hypertension? Microvasc Res 90, 135-137 (2013).
23. Materazzi, S., et al. Vasodilator activity of hydrogen sulfide (H(2)S) in human mesenteric arteries. Microvasc Res 109, 38-44 (2017).
24. Cacanyiova, S., et al. Nitroso-sulfide coupled signaling triggers specific vasoactive effects in the intrarenal arteries of patients with arterial hypertension. J Physiol Pharmacol 68, 527-538 (2017).
25. Cindrova-Davies, T., et al. Reduced cystathionine gamma-lyase and increased miR-21 expression are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator. Am J Pathol 182, 1448-1458 (2013).
26. Wang, M., Guo, Z. & Wang, S. Regulation of cystathionine gamma-lyase in mammalian cells by hypoxia. Biochem Genet 52, 29-37 (2014).
27. Tran, B.H., et al. Cardioprotective effects and pharmacokinetic properties of a controlled release formulation of a novel hydrogen sulfide donor in rats with acute myocardial infarction. Biosci Rep 35(2015).
28. Mistry, R.K., et al. Transcriptional Regulation of Cystathionine-gamma-Lyase in Endothelial Cells by NADPH Oxidase 4-Dependent Signaling. J Biol Chem 291, 1774-1788 (2016).
29. Magierowski, M., et al. Exogenous and Endogenous Hydrogen Sulfide Protects Gastric Mucosa against the Formation and Time-Dependent Development of Ischemia/Reperfusion-Induced Acute Lesions Progressing into Deeper Ulcerations. Molecules 22(2017).
30. Sun, H., Qi, L., Wang, S., Li, X. & Li, C. Hydrogen sulfide is expressed in the human and the rat cultured nucleus pulposus cells and suppresses apoptosis induced by hypoxia. PLoS One 13, e0192556 (2018).
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