GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia

Lilyanna, Shera; Peh, Meng Teng; Liew, Oi Wah; Wang, Peipei; Moore, Philip K.; Richards, A. Mark; Martinez, Eliana C.

doi:10.1016/j.yjmcc.2015.07.028

Cited by 42 publications

(35 citation statements)

References 49 publications

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“…Several in vivo studies have demonstrated that exogenously administered H 2 S protects against myocardial infarction (Johansen et al, 2006;Calvert et al, 2009Calvert et al, , 2010Szabó et al, 2011;King et al, 2014;Zhang et al, 2014;Lilyanna et al, 2015). Different laboratories have studied NaHS, Na2S, GYY4137, diallyl trisulfide, adenine analogs, or N-mercapto-based agents and have found them to be protective (Bibli et al, 2015;Zhao et al, 2015;Lougiakis et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Chatzianastasiou

Bibli²,

Andreadou³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Hydrogen sulfide (H 2 S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H 2 S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H 2 S donors from different classes and studies their mechanisms of action in myocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H 2 O 2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na 2 S), thiovaline (TV), GYY4137[morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate], and AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)-phenoxy)decyl) triphenylphospho-nium bromide]. Inhibition of nitric oxide (NO) synthesis prevented the cytoprotective effects of Na 2 S and TV, but not GYY4137 and AP39, against H 2 O 2 -induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H 2 S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na 2 S. Moreover, Na 2 S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na 2 S and AP39 reduced infarct size in mice lacking cyclophilin-D (CypD), a modulator of the mitochondrial permeability transition pore (PTP). Nevertheless, only AP39 displayed a direct effect on mitochondria by increasing the mitochondrial Ca 21 retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H 2 S donors we tested limited infarct size, the pathways involved were not conserved. Na 2 S had no direct effects on PTP opening, and its action was nitric oxide dependent. In contrast, the cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.

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Section: Discussionmentioning

confidence: 99%

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Chatzianastasiou

Bibli²,

Andreadou³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…H 2 S could reduce myocardial remodeling caused by myocardial ischemia by increasing the activity of natriuretic peptide and improve myocardial remodeling by inhibiting myocardial fibroblast cell migration to myocardial fibroblasts (Lilyanna et al, 2015; Zhang et al, 2015). In smoking rat model and heart failure rat model, H 2 S also reduced myocardial remodeling and improved cardiac function (Mishra et al, 2010; Zhou et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Inhibits High-Salt Diet-Induced Myocardial Oxidative Stress and Myocardial Hypertrophy in Dahl Rats

et al. 2017

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The study aimed to examine the protective effect of hydrogen sulfide (H2S) on high-salt-induced oxidative stress and myocardial hypertrophy in salt-sensitive (Dahl) rats. Thirty male Dahl rats and 40 SD rats were included in the study. They were randomly divided into Dahl control (Dahl + NS), Dahl high salt (Dahl + HS), Dahl + HS + NaHS, SD + NS, SD + HS, SD + HS + NaHS, and SD + HS + hydroxylamine (HA). Rats in Dahl + NS and SD + NS groups were given chow with 0.5% NaCl and 0.9% normal saline intraperitoneally daily. Myocardial structure, α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) expressions were determined. Endogenous myocardial H2S pathway and oxidative stress in myocardial tissues were tested. Myocardial H2S pathway was downregulated with myocardial hypertrophy featured by increased heart weight/body weight and cardiomyocytes cross-sectional area, decreased α-MHC and increased β-MHC expressions in Dahl rats with high-salt diet (all P < 0.01), and oxidative stress in myocardial tissues was significantly activated, demonstrated by the increased contents of hydroxyl radical, malondialdehyde and oxidized glutathione and decreased total antioxidant capacity, carbon monoxide, catalase, glutathione, glutathione peroxidase, superoxide dismutase (SOD) activities and decreased SOD1 and SOD2 protein expressions (P < 0.05, P < 0.01). However, H2S reduced myocardial hypertrophy with decreased heart weight/body weight and cardiomyocytes cross-sectional area, increased α-MHC, decreased β-MHC expressions and inhibited oxidative stress in myocardial tissues of Dahl rats with high-salt diet. However, no significant difference was found in H2S pathway, myocardial structure, α-MHC and β-MHC protein and oxidative status in myocardial tissues among SD + NS, SD + HS, and SD + HS + NaHS groups. HA, an inhibitor of cystathionine β-synthase, inhibited myocardial H2S pathway (P < 0.01), and stimulated myocardial hypertrophy and oxidative stress in SD rats with high-salt diet. Hence, H2S inhibited myocardial hypertrophy in high salt-stimulated Dahl rats in association with the enhancement of antioxidant capacity, thereby inhibiting oxidative stress in myocardial tissues.

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“…The major biologic effects included cytoprotection, i.e., improvement in cell viability, mitochondrial function, and overall cell survival in various cultured cells exposed to various reactive oxidant species, or to hypoxia, or to proinflammatory mediators. In vivo studies demonstrated the protective effect of GYY4137 in various models of ischemia-reperfusion and organ injury (myocardial, renal, hepatic) against early onset cell death and later-onset organ fibrosis (Lilyanna et al, 2015;Meng et al, 2015b,c;Zheng et al, 2015;Chatzianastasiou et al, 2016;Karwi et al, 2016). GYY4137 was also found to attenuate both hyperoxic and aortic cross-clamping-induced lung injury (Madurga et al, 2014;Vadivel et al, 2014;Tang et al, 2017) and atherosclerosis and other forms of endothelial dysfunction and vascular remodeling (Liu et al, 2013;Wang et al, 2009b;Xu et al, 2014;Candela et al, 2016;Nußbaum et al, 2017;Weber et al, 2017).…”

Section: Figmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H₂S Levels: H₂S Donors and H₂S Biosynthesis Inhibitors

2017

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Over the last decade, hydrogen sulfide (HS) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, HS is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. HS levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of HS, either based on HS donation or inhibition of HS biosynthesis. HS donation can be achieved through the inhalation of HS gas and/or the parenteral or enteral administration of so-called fast-releasing HS donors (salts of HS such as NaHS and NaS) or slow-releasing HS donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated HS release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with HS-donating groups (the most advanced compound in clinical trials is ATB-346, an HS-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of HS synthesis, there are now several small molecule compounds targeting each of the three HS-producing enzymes cystathionine--synthase (CBS), cystathionine--lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous HS production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known HS donors and HS biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

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GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia

Cited by 42 publications

References 49 publications

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Hydrogen Sulfide Inhibits High-Salt Diet-Induced Myocardial Oxidative Stress and Myocardial Hypertrophy in Dahl Rats

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H₂S Levels: H₂S Donors and H₂S Biosynthesis Inhibitors

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GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia

Cited by 42 publications

References 49 publications

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Hydrogen Sulfide Inhibits High-Salt Diet-Induced Myocardial Oxidative Stress and Myocardial Hypertrophy in Dahl Rats

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

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International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H₂S Levels: H₂S Donors and H₂S Biosynthesis Inhibitors