Review articleCystathionine beta-Synthase in hypoxia and ischemia/reperfusion: A current overview
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.
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