Review article
Cystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview

https://doi.org/10.1016/j.abb.2022.109149Get rights and content

Abstract

Besides its presence in the liver, brain, pancreas, and kidney, Cystathionine beta-Synthase (CBS) is also found in many other tissues, where it acts through regulation of hydrogen sulfide (H2S) generation and homocysteine (Hcy) metabolism, to interact with other molecules during hypoxia and ischemia/reperfusion (I/R). Despite all the advances accumulated in decades of research on CBS, there are still controversies, and the role of CBS in many tissues during hypoxia and I/R is still unclear. Herein, we overviewed the expression level, the role, and the mechanism through which CBS interacts with other molecules during hypoxia and I/R processes in tissues of humans and other organisms. CBS appeared to be deregulated under hypoxia and I/R, after which it mostly conduces the reparation in the concerned tissue after damage; however, it has been described that CBS could also play pathological effects (exacerbating the damage). From all findings, it emerges that variations in CBS expression in these conditions depend on the organism, tissue, or subcellular localization, CBS could play both protective and pathological effects; and artificially controlling CBS expression may help to provide novel strategies for treatment or prevention of hypoxia and I/R -related injury.

Introduction

Cystathionine beta-Synthase (CBS) is the pivotal enzyme of the transsulfuration pathway [1,2]. CBS catalysis the irreversible condensation of homocysteine (Hcy) into cystathionine, and contributes to the endogenous production of hydrogen sulfide (H2S) using cysteine (Cys) and Hcy as substrates, through the desulfuration reaction [[3], [4], [5]]. Although CBS is mainly expressed in the brain tissue [6], an important number of studies reported its expression and activity in many other tissues in humans and other organisms [[6], [7], [8], [9], [10], [11]]. Changes in CBS expression are associated with changes in Hcy and H2S levels, resulting in various pathological disorders in the biological system (brain and heart tissues, and immune system) and participate in the diseases (such as homocystinuria and cancers) progression. CBS deficiency is the main cause of homocystinuria, which is associated with mental retardation [12] and vascular disease [13], while its overexpression can cause developmental abnormality, resulting in cognitive disorder in down syndrome [1]. Numerous studies demonstrated the role of CBS in hypoxia and ischemia/reperfusion (I/R) conditions, mainly through H2S production or Hcy metabolism, contributing to the response against hypoxia or I/R-induced injury [10,[14], [15], [16], [17], [18], [19], [20], [21]]. Herein, we aimed to overview, based on literature, the expression level, the physiological and pathological role, and the mechanism of action of CBS in the hypoxia and I/R processes in different tissues in human and other organisms. Understanding all these mechanisms may help to find the optimal strategy or to adapt the existing strategies, to overcome, or better, to prevent the hypoxia and I/R injury.

Section snippets

CBS tissue distribution

The transsulfuration pathway was discovered in 1934 by du Vigneaud et al. [22]. The enzymatic processes involving CBS were discovered in 1965 [6] and 1982 [4]. CBS was mapped on human chromosome 21q22.3 and mouse chromosome 17 region A-C [23]. Human CBS was entirely cloned and sequenced by Kraus et al. and Chassé et al. and for the rat, it was later cloned and sequenced by Swaroop et al. [[24], [25], [26]]. The results showed that CBS is made of 551 amino acids [24] and it is expressed in the

The role of CBS/H2S in ischemic stroke

H2S in the brain is mainly produced by CBS [35,36,39]. It has been reported that H2S can play a neuroprotective effect in neurodegeneration and neurovascular dysfunction whether it is endogenous or exogenously administrated (through NaHS, a H2S donor) [[38], [39], [40]]. In CBS deficient (obviously associated with low generation of H2S) mice exposed to ischemia (induced by middle cerebral artery occlusion (MCAO)), the activation of the nuclear factor kappa-B (NF-kB; an important regulatory

CBS/H2S and hypoxia-induced apoptosis

An in-vitro study [71] reported that under hypoxia (OGD condition), the expression level of miR-125b-5p in PC12 cells is significantly (p < 0.05) increased ∼35%. It was found that the overexpressed miR-125b-5p markedly decreased (p < 0.001) the mRNA and protein levels of CBS by ∼49% and ∼68% (following 8 h of hypoxia) compared to control group respectively. The resulting reduction in H2S generation could increase LDH activity [71], as it has been demonstrated that exogenous H2S could have the

Conclusion

All the studies included in our study show evidence that CBS expression is deregulated during hypoxia and ischemia/reperfusion, which modulates H2S generation and Hcy metabolism. Most studies reported a decreased level of CBS during hypoxia and ischemia/reperfusion associated with decreased H2S generation and Hcy metabolism, resulting in hyperhomocysteinemia, which exacerbates the following injury. Intriguingly, there are studies reporting an increase in CBS level during hypoxia and

Statement of ethics

The authors have no ethical conflicts to disclose.

Funding sources

This work was supported by the National Natural Science Foundation of China (Nos. 30671803 and 81273174), the Natural Science Foundation of Heilongjiang Province (No. LH2020H007), the Supporting Plan Project for Youth Academic Backbone of General Colleges and Universities of Heilongjiang Province (No.1253G058), Heilongjiang Innovation and Entrepreneurship Training Scheme for university students (201910222062), and North Medicine and Functional Food Characteristic Subject Project in Heilongjiang

Author contributions

M.O. wrote the manuscript. N.L., Y.H., N.L., M.G., C.M., and L.Z. proofread the manuscript. H.A.-W. revised the manuscript, and X.H. supervised the manuscript. All authors reviewed and approved the final manuscript.

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgment

We would like to acknowledge the National Natural Science Foundation of China, the Natural Science Foundation of Heilongjiang Province, the Supporting Plan Project for Youth Academic Backbone of General Colleges and Universities of Heilongjiang Province, Heilongjiang Innovation and Entrepreneurship Training Scheme for university students, and North Medicine and Functional Food Characteristic Subject Project in Heilongjiang Province.

References (88)

  • James D. Finkelstein

    Methionine metabolism in mammals

    J. Nutr. Biochem.

    (1990)
  • C. Persa et al.

    The distribution of cystathionine beta-synthase (CBS) in the eye: implication of the presence of a trans-sulfuration pathway for oxidative stress defense

    Exp. Eye Res.

    (2006 Oct)
  • S. Sen et al.

    A novel oncometabolite in human breast cancer

    Arch. Biochem. Biophys.

    (2016 Aug 15)
  • C. Ren et al.

    Dynamic change of hydrogen sulfide during global cerebral ischemia-reperfusion and its effect in rats

    Brain Res.

    (2010 Jul 23)
  • L. Tao et al.

    Preconditioning with hydrogen sulfide ameliorates cerebral ischemia/reperfusion injury in a mouse model of transient middle cerebral artery occlusion

    Chem. Biol. Interact.

    (2019 Sep 1)
  • J.J. Bruintjes et al.

    Hippocampal cystathionine beta synthase in young and aged mice

    Neurosci. Lett.

    (2014 Mar 20)
  • P.K. Kamat et al.

    Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice

    Neuroscience

    (2013 Nov 12)
  • M. Zhang et al.

    The cystathionine β-synthase/hydrogen sulfide pathway contributes to microglia-mediated neuroinflammation following cerebral ischemia

    Brain Behav. Immun.

    (2017 Nov)
  • Y. Liu et al.

    Electro-acupuncture protects against hypoxic-ischemic brain-damaged immature rat via hydrogen sulfide as a possible mediator

    Neurosci. Lett.

    (2010 Nov 12)
  • P. Sachdev

    Homocysteine, cerebrovascular disease and brain atrophy

    J. Neurol. Sci.

    (2004 Nov 15)
  • P.S. Sachdev

    Homocysteine and brain atrophy

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2005 Sep)
  • B. Geng et al.

    H2S generated by heart in rat and its effects on cardiac function

    Biochem. Biophys. Res. Commun.

    (2004 Jan 9)
  • N. Wu et al.

    Ischemia/reperfusion reduces transcription factor Sp1-mediated cystathionine beta-synthase expression in the kidney

    J. Biol. Chem.

    (2010 Jun 11)
  • T.K. Ho et al.

    Increased endogenous angiogenic response and hypoxia-inducible factor-1alpha in human critical limb ischemia

    J. Vasc. Surg.

    (2006 Jan)
  • Y. Shen et al.

    MiR-125b-5p is involved in oxygen and glucose deprivation injury in PC-12 cells via CBS/H2S pathway

    Nitric Oxide

    (2018 Aug 1)
  • L. Li et al.

    Exogenous H2S contributes to recovery of ischemic post-conditioning-induced cardioprotection by decrease of ROS level via down-regulation of NF-κB and JAK2-STAT3 pathways in the aging cardiomyocytes

    Cell Biosci.

    (2016 Apr 18)
  • A.A. Untereiner et al.

    H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates cellular bioenergetics in HCT116 colon cancer cells

    Biochem. Pharmacol.

    (2017 Jul 15)
  • A.F. Donatti et al.

    Involvement of endogenous hydrogen sulfide (H2S) in the rostral ventrolateral medulla (RVLM) in hypoxia-induced hypothermia

    Brain Res. Bull.

    (2014 Sep)
  • M. Kwiatkoski et al.

    Hydrogen sulfide as a cryogenic mediator of hypoxia-induced anapyrexia

    Neuroscience

    (2012 Jan 10)
  • A.F. Donatti et al.

    Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Bötzinger complex downregulates ventilatory responses to hypoxia

    Respir. Physiol. Neurobiol.

    (2014 Aug 15)
  • H. Zhu et al.

    Cystathionine β-Synthase in Physiology and Cancer

    Biomed. Res. Int.

    (2018 Jun 28)
  • M.H. Stipanuk et al.

    Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat

    Biochem. J.

    (1982 Aug 15)
  • K. Abe et al.

    The possible role of hydrogen sulfide as an endogenous neuromodulator

    J. Neurosci.

    (1996 Feb 1)
  • G.A. Prathapasinghe et al.

    Detrimental role of homocysteine in renal ischemia-reperfusion injury

    Am. J. Physiol. Ren. Physiol.

    (2007 May)
  • D. Gersztenkorn et al.

    Hydrogen sulfide contributes to retinal neovascularization in ischemia-induced retinopathy

    Invest. Ophthalmol. Vis. Sci.

    (2016 Jun 1)
  • K.N. Islam et al.

    Hydrogen sulfide levels and nuclear factor-erythroid 2-related factor 2 (NRF2) activity are attenuated in the setting of critical limb ischemia (CLI)

    J. Am. Heart Assoc.

    (2015 May 14)
  • G. Turner et al.

    Homocystinuria : a report of two Australian families: Aust

    Paediatric J.

    (1967)
  • D.E. Wilcken et al.

    The natural history of vascular disease in homocystinuria and the effects of treatment

    J. Inherit. Metab. Dis.

    (1997 Jun)
  • S.J. Han et al.

    Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury

    Nephrol. Dial. Transplant.

    (2015 Sep)
  • P. Wang et al.

    Downregulation of cystathionine β-synthase and cystathionine γ-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury

    Phys. Rep.

    (2014 Dec 24)
  • H. Wang et al.

    Hydrogen sulfide restores cardioprotective effects of remote ischemic preconditioning in aged rats via HIF-1α/Nrf2 signaling pathway

    KOREAN J. PHYSIOL. PHARMACOL.

    (2021 May 1)
  • V. López et al.

    Activation of arginase II by asymmetric dimethylarginine and homocysteine in hypertensive rats induced by hypoxia: a new model of nitric oxide synthesis regulation in hypertensive processes?

    Hypertens. Res.

    (2021 Mar)
  • R. Zhang et al.

    Excessive nNOS/NO/AMPK signaling activation mediated by the blockage of the CBS/H2S system contributes to oxygen-glucose deprivation-induced endoplasmic reticulum stress in PC12 cells

    Int. J. Mol. Med.

    (2017 Aug)
  • Vigneaud Du et al.

    The oxidation of the sulfur of homocystine, methionine, and S-methyl-cysteine in the animal body

    J. Biol. Chem.

    (1934)
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