Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells

Yang, Guangdong; Wu, Lingyun; Bryan, Sean; Khaper, Neelam; Mani, Sarathi; Wang, Rui

doi:10.1093/cvr/cvp420

Cited by 143 publications

(175 citation statements)

References 36 publications

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“…In each cell type studied, we also demonstrate that H2S inhibits proliferation, consistent with a previous report in rat aortic A10 smooth muscle [21]. Our results are also consistent with the observation that VSMCs isolated from CSE -/-mice show increased proliferation compared to wild type (WT) VSMCs, further indicating that H2S has a 'breaking' effect on proliferation [41]. The major and unexpected finding of the present study, however, is that H2S appears to suppress proliferation independent of any action on T-type Ca 2+ channels.…”

Section: Resultssupporting

confidence: 92%

H2S does not regulate proliferation via T-type Ca2+ channels

Elíes

Johnson

Boyle

et al. 2015

Biochemical and Biophysical Research Communications

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T-type Ca 2+ channels (Cav3.1, 3.2 and 3.3) strongly influence proliferation of various cell types, including vascular smooth muscle cells (VSMCs) and certain cancers. We have recently shown that the gasotransmitter carbon monoxide (CO) inhibits T-type Ca 2+ channels and, in so doing, attenuates proliferation of VSMC. We have also shown that the T-type Ca 2+ channel Cav3.2 is selectively inhibited by hydrogen sulfide (H2S) whilst the other channel isoforms (Cav3.1 and Cav3.3) are unaffected. Here, we explored whether inhibition of Cav3.2 by H2S could account for the anti-proliferative effects of this gasotransmitter. H2S suppressed proliferation in HEK293 cells expressing Cav3.2, as predicted by our previous observations. However, H2S was similarly effective in suppressing proliferation in wild type (non-transfected) HEK293 cells and those expressing the H2S insensitive channel, Cav3.1. Further studies demonstrated that T-type Ca 2+ channels in the smooth muscle cell line A7r5 and in human coronary VSMCs strongly influenced proliferation. In both cell types, H2S caused a concentration-dependent inhibition of proliferation, yet by far the dominant T-type Ca 2+ channel isoform was the H2S-insensitive channel, Cav3.1.Our data indicate that inhibition of T-type Ca 2+ channel-mediated proliferation by H2S is independent of the channels' sensitivity to H2S.

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Section: Resultssupporting

confidence: 92%

H2S does not regulate proliferation via T-type Ca2+ channels

Elíes

Johnson

Boyle

et al. 2015

Biochemical and Biophysical Research Communications

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“…On the other hand, CSE appears to be the enzyme predominantly involved in endogenous H 2 S production in rodent smooth muscle and the lung (3,17,35,40,41). The work presented here is the first of its kind in human ASM cells.…”

Section: Europe Pmc Funders Author Manuscriptsmentioning

confidence: 69%

Hydrogen Sulfide Inhibits Proliferation and Release of IL-8 from Human Airway Smooth Muscle Cells

Perry

Hui

Whiteman

et al. 2010

Free Radical Biology and Medicine

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Hydrogen sulfide (H 2 S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-β-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H 2 S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1β. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H 2 S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H 2 S, increased DNA synthesis induced by FCS and IL-1β. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1β, indicating a role for endogenous H 2 S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H 2 S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H 2 S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H 2 S production. Finally, we found that exogenous H 2 S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H 2 S inhibited cellular proliferation and IL-8 release. In summary, H 2 S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H 2 S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.Keywords hydrogen sulfide; airway smooth muscle; cystathionine-γ-lyase; cystathionine-β-synthase; extracellular signal-regulated kinase-1/2Correspondence and requests for reprints should be addressed to Kian Fan Chung, M.D., D.Sc., Airways Disease, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. f.chung@imperial.ac.uk. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Author Disclosure: K.F.C. serves on the advisory board of GlaxoSmith Kline, Gilead, and Boehringer Ingelheim and received lecture fees from Glaxo-SmithKline, Novartis, and AstraZeneca.None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Hydrogen sulfide (H 2 S), first discovered in human tissues over 10 years ago, has emerged as an important gaseous mediator in cellular physiology and pathology, being involved in several processes, including chronic inflammation, learning and memory, and regulation of blood pressure (1). H 2 S is now considered as the third member of a family of gasotransmitters, together with nitric oxide (NO) and carbon monoxide (2). The bulk of endogenous H 2 S synthesis in mammalian tissues appears to be from the pyrid...

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“…The ERK1/2 activation has been shown to be increased (42)(43)(44)(45)(46), decreased (22,23,29,(47)(48)(49) or unaltered (50,51) following exposure to H 2 S. In the present study, we provide clear evidence that the activation of ERK1/2 contributes to HG-induced injury in H9c2 cells and that exogenous H 2 S protects H9c2 cells against HG-induced injury by inhibiting ERK1/2 activation, which is supported by our previous study [Dong et al (23)]. Although the mechanisms through which ERK1/2 induces either cell death or survival and the reasons for the differential effects induced by exogenous H 2 S on the activation of ERK1/2 are unclear, it is generally accepted that the duration and magnitude of ERK1/2 activation may be an important factor in determining cell survival or apoptosis (52).…”

Section: Discussionmentioning

confidence: 99%

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

Wang

Chen

et al. 2013

International Journal of Molecular Medicine

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Abstract. Hyperglycemia is a risk factor for the development of diabetic cardiovascular complications, which are associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we demonstrate the inhibitory effects of exogenous hydrogen sulfide (H 2 S) on the activation of the MAPK pathway. The aim of the present study was to determine whether exogenous H 2 S prevents high glucose (HG)-induced injury by inhibiting the activation of the p38 MAPK and extracellular signal-regulated kinase (ERK)1/2 (members of MAPK) pathways in cardiomyoblasts (H9c2 cells). The findings of the present study demonstrated that the treatment of H9c2 cells with HG (35 mM glucose) for 24 h not only significantly induced injury, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP), but also upregulated the expression levels of phosphorylated (p)-p38 MAPK and p-ERK1/2. The increased expression levels of p-p38 MAPK and p-ERK1/2 were markedly reduced by pre-treatment of the H9c2 cells with 400 µM sodium hydrogen sulfide (NaHS; a donor of H 2 S) prior to exposure to 35 mM glucose. Importantly, pre-treatment of the cells with 400 µM NaHS or 3 µM SB203580 (a selective inhibitor of p38 MAPK) or 15 µM U0126 (a selective inhibitor of ERK1/2) attenuated the HG-induced cardiomyocyte injury, leading to an increase in cell viability and a decrease in the number of apoptotic cells, preventing ROS generation, as well as the loss of MMP. In addition, pre-treatment of the cells with 1,000 µM N-acetyl-L-cysteine (a ROS scavenger) prior to exposure to HG ameliorated the HG-induced cytotoxicity. Taken together, the data from the present study demonstrate for the first time, to our knowledge, that exogenous H 2 S exerts a protective effect against HG-induced injury by inhibiting the activation of the p38 MAPK and ERK1/2 pathways and preventing oxidative stress in H9c2 cells.

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Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells

Cited by 143 publications

References 36 publications

H2S does not regulate proliferation via T-type Ca2+ channels

H2S does not regulate proliferation via T-type Ca2+ channels

Hydrogen Sulfide Inhibits Proliferation and Release of IL-8 from Human Airway Smooth Muscle Cells

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

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