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ABSTRACT: Hydrogen sulfide (H2S) therapy protects non-diabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine if H2S therapy provides cardioprotection in the setting of Type-2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 hours or 7 days prior to myocardial ischemia significantly decreased myocardial injury in db/db diabetic mice (12 weeks of age). In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, we focused on the role of Nrf2 signaling. Our results indicate that diabetes does not alter the ability of H2S to increase the nuclear localization of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of NADPH;quinine oxidoreductase 1 (NQO1) was increased after the acute treatment, whereas the expression of heme-oxygenase-1 (HO-1) was only increased after 7 days of treatment. This discrepancy was found to be the result of an increased nuclear expression of Bach1, a known repressor of HO-1 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further analysis, revealed that 7 days of Na2S treatment overcame this impairment by removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings demonstrate for the first time that exogenous administration of Na2S attenuates myocardial ischemia-reperfusion injury in db/db mice suggesting the potential therapeutic effects of H2S in treating a heart attack in the setting of Type-2 diabetes.
AJP Heart and Circulatory Physiology 03/2013; · 3.71 Impact Factor
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Kazuhisa Kondo,
Shashi Bhushan,
Adrienne L King,
Sumanth D Prabhu,
Tariq Hamid,
Steven Koenig,
Toyoaki Murohara,
Benjamin L Predmore,
Gabriel Gojon,
Rui Wang,
Naveena Karusula,
Chad K Nicholson, John W Calvert,
David J Lefer
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ABSTRACT: BACKGROUND: Cystathionine gamma-lyase (CSE) produces H(2)S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H(2)S therapy in the setting of pressure overload-induced heart failure. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel H(2)S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H(2)S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H(2)S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. CONCLUSIONS: Our results demonstrate that H(2)S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure and oral H(2)S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase (eNOS) and increased NO bioavailability.
Circulation 02/2013; · 14.74 Impact Factor
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ABSTRACT: OBJECTIVE: The aim of this study was to determine whether thioredoxin 1 (Trx1) mediates the cardioprotective effects of hydrogen sulfide (H(2)S) in a model of ischemic-induced heart failure (HF).Approach and Results-Mice with a cardiac-specific overexpression of a dominant negative mutant of Trx1 and wild-type littermates were subjected to ischemic-induced HF. Treatment with H(2)S as sodium sulfide (Na(2)S) not only increased the gene and protein expression of Trx1 in the absence of ischemia but also augmented the HF-induced increase in both. Wild-type mice treated with Na(2)S experienced less left-ventricular dilatation, improved left-ventricular function, and less cardiac hypertrophy after the induction of HF. In contrast, Na(2)S therapy failed to improve any of these parameters in the dominant negative mutant of Trx1 mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na(2)S therapy inhibited HF-induced apoptosis signaling kinase-1 signaling and nuclear export of histone deacetylase 4 in a Trx1-dependent manner. CONCLUSIONS: These findings provide novel information that the upregulation of Trx1 by Na(2)S therapy in the setting of HF sets into motion events, such as the inhibition of apoptosis signaling kinase-1 signaling and histone deacetylase 4 nuclear export, which ultimately leads to the attenuationof left-ventricular remodeling.
Arteriosclerosis Thrombosis and Vascular Biology 01/2013; · 6.37 Impact Factor
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Hee Yun Suk,
Chen Zhou,
Teddy T C Yang,
Hong Zhu,
Raymond Y L Yu,
Opeyemi Olabisi,
Xiaoyong Yang,
Deborah Brancho,
Ja-Young Kim,
Philipp E Scherer,
Philippe G Frank,
Michael P Lisanti, John W Calvert,
David J Lefer,
Jeffery D Molkentin,
Alessandra Ghigo,
Emilio Hirsch,
Jianping Jin,
Chi-Wing Chow
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ABSTRACT: Insulin resistance, hyperlipidemia and cardiovascular complications are common dysregulations of metabolic syndrome. Transplant patients treated with immunosuppressant drugs such as cyclosporine A (CsA), an inhibitor of calcineurin phosphatase, frequently develop similar metabolic complications. While calcineurin is known to mediate insulin sensitivity by regulating β-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Aβ (CnAβ-/-). We show that mice lacking calcineurin Aβ are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAβ-/- mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by β-adrenergic G-protein coupled receptor signaling pathways. CnAβ-/- mice also exhibit additional pathophysiological phenotypes due to the potentiated GPCR signaling pathways. A cell autonomous mechanism with sustained cAMP/PKA activation is found in CnAβ-/- mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAβ-/- mice, however, are sensitive to phosphodiesterase inhibitor. Indeed, we show that calcineurin regulates degradation of phosphodiesterase 3B (PDE3B), in addition to PDE4D. These results establish a role of calcineurin in lipid homeostasis. These data also indicate that potentiated cAMP signaling pathway may provide an alternative molecular pathogenesis for the metabolic complications elicited by CsA in transplant patients.
Journal of Biological Chemistry 12/2012; · 4.77 Impact Factor
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International journal of vascular medicine 01/2012; 2012:396369.
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The Journal of Physiology 12/2011; 589(Pt 24):5919-20. · 4.72 Impact Factor
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Juan P Aragón,
Marah E Condit,
Shashi Bhushan,
Benjamin L Predmore,
Sandeep S Patel,
D Bennett Grinsfelder,
Susheel Gundewar,
Saurabh Jha, John W Calvert,
Lili A Barouch,
Madhav Lavu,
Harold M Wright,
David J Lefer
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ABSTRACT: This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction.
Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability.
Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels.
Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR (-/-), eNOS(-/-), and in nNOS(-/-) mice.
Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.
Journal of the American College of Cardiology 12/2011; 58(25):2683-91. · 14.16 Impact Factor
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John W Calvert,
Marah E Condit,
Juan Pablo Aragón,
Chad K Nicholson,
Bridgette F Moody,
Rebecca L Hood,
Amy L Sindler,
Susheel Gundewar,
Douglas R Seals,
Lili A Barouch,
David J Lefer
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ABSTRACT: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role.
To determine the role of β(3)-adrenergic receptors (β(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise.
Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by β(3)-AR stimulation and that in response to exercise a deficiency of β(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury.
Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of β(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).
Circulation Research 06/2011; 108(12):1448-58. · 9.49 Impact Factor
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Ruifeng Teng, John W Calvert,
Nathawut Sibmooh,
Barbora Piknova,
Norio Suzuki,
Junhui Sun,
Kevin Martinez,
Masayuki Yamamoto,
Alan N Schechter,
David J Lefer,
Constance Tom Noguchi
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ABSTRACT: Increasing evidence indicates that high levels of serum erythropoietin (Epo) can lessen ischemia-reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect. To clarify the mechanisms underlying this cardioprotection, we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells (ΔEpoR). Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase (eNOS) activity in vitro and in vivo, and enhanced nitric oxide (NO) production that was determined directly by real-time measurements of gaseous NO release. Epo stimulated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathways, and inhibition of PI3K, but not MEK activity, blocked Epo-induced NO production. To verify the potential of this Epo effect in cardioprotection in vivo, ΔEpoR-mice with Epo response in heart restricted to endothelium were treated with Epo. These mice exhibited a similar increase in eNOS phosphorylation in coronary artery endothelium as that found in wild type (WT) mice. In addition, in both WT- and ΔEpoR-mice, exogenous Epo treatment prior to myocardial ischemia provided comparable protection. These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect. The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection.
Archiv für Kreislaufforschung 02/2011; 106(3):343-54. · 7.35 Impact Factor
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ABSTRACT: We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD) (71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ∼100-300% greater and SOD activity was ∼50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.
Aging cell 01/2011; 10(3):429-37. · 7.55 Impact Factor
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ABSTRACT: Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously produced gaseous messenger molecules collectively known as gasotransmitters. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. Specifically, when used at physiological levels, the exogenous and endogenous manipulation of these three gases has been shown to modulate ischemia/reperfusion injury by inducing a number of cytoprotective mechanisms including: induction of vasodilatation, inhibition of apoptosis, modulation of mitochondrial respiration, induction of antioxidants, and inhibition of inflammation. However, while the actions are similar, there are some differences in the mechanisms by which these gasotransmitters induce these effects and the regulatory actions of the enzyme systems can vary depending upon the gas being investigated. Furthermore, there does appear to be some crosstalk between the gases, which can provide synergistic effects and additional regulatory effects. This review article will discuss several models and mechanisms of gas-mediated cytoprotection, as well as provide a brief discussion on the complex interactions between the gasotransmitter systems.
Medical gas research. 01/2011; 1(1):3.
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ABSTRACT: Gasotransmitters are lipid soluble, endogenously produced gaseous signaling molecules that freely permeate the plasma membrane of a cell to directly activate intracellular targets, thus alleviating the need for membrane-bound receptors. The gasotransmitter family consists of three members: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H(2)S). H(2)S is the latest gasotransmitter to be identified and characterized and like the other members of the gasotransmitter family, H(2)S was historically considered to be a toxic gas and an environmental/occupational hazard. However with the discovery of its presence and enzymatic production in mammalian tissues, H(2)S has gained much attention as a physiological signaling molecule. Also, much like NO and CO, H(2)S's role in ischemia/reperfusion (I/R) injury has recently begun to be elucidated. As such, modulation of endogenous H(2)S and administration of exogenous H(2)S has now been demonstrated to be cytoprotective in various organ systems through diverse signaling mechanisms. This review will provide a detailed description of the role H(2)S plays in different model systems of I/R injury and will also detail some of the mechanisms involved with its cytoprotection.
Pharmacological Research 10/2010; 62(4):289-97. · 4.44 Impact Factor
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Radhika H Muzumdar,
Derek M Huffman, John W Calvert,
Saurabh Jha,
Yoni Weinberg,
Lingguang Cui,
Anjana Nemkal,
Gil Atzmon,
Laura Klein,
Susheel Gundewar,
Sang Yong Ji,
Madhav Lavu,
Benjamin L Predmore,
David J Lefer
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ABSTRACT: Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion.
Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro.
These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.
Arteriosclerosis Thrombosis and Vascular Biology 10/2010; 30(10):1940-8. · 6.37 Impact Factor
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John W Calvert
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ABSTRACT: Exercise training has been shown to reduce many risk factors related to cardiovascular disease, including high blood pressure, high cholesterol, obesity, and insulin resistance. More importantly, exercise training has been consistently shown to confer sustainable protection against myocardial infarction in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise training is able to protect the heart, but some studies have suggested that it increases a number of classical signalling molecules. For instance, exercise can increase components of the endogenous antioxidant defences (i.e. superoxide dismutase and catalase), increase the expression of heat shock proteins, activate ATP-sensitive potassium (K(ATP)) channels, and increase the expression and activity of endothelial nitric oxide (NO) synthase resulting in an increase in NO levels. This review article will provide a brief summary of the role that these signalling molecules play in mediating the cardioprotective effects of exercise. In particular, it will highlight the role that NO plays and introduce the idea that the stable NO metabolite, nitrite, may play a major role in mediating these cardioprotective effects.
Cardiovascular research 09/2010; 89(3):499-506. · 5.80 Impact Factor
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Hong Zhu,
Hee Yun Suk,
Raymond Y L Yu,
Deborah Brancho,
Opeyemi Olabisi,
Teddy T C Yang,
XiaoYong Yang,
Jialin Zhang,
Mustapha Moussaif,
Jorge L Durand, [......],
Michael P Lisanti, John W Calvert,
Mark R Duranski,
David J Lefer,
Elaine Huston,
George S Baillie,
Miles D Houslay,
Jeffrey D Molkentin,
Jianping Jin,
Chi-Wing Chow
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ABSTRACT: Calcineurin is a widely expressed and highly conserved Ser/Thr phosphatase. Calcineurin is inhibited by the immunosuppressant drug cyclosporine A (CsA) or tacrolimus (FK506). The critical role of CsA/FK506 as an immunosuppressant following transplantation surgery provides a strong incentive to understand the phosphatase calcineurin. Here we uncover a novel regulatory pathway for cyclic AMP (cAMP) signaling by the phosphatase calcineurin which is also evolutionarily conserved in Caenorhabditis elegans. We found that calcineurin binds directly to and inhibits the proteosomal degradation of cAMP-hydrolyzing phosphodiesterase 4D (PDE4D). We show that ubiquitin conjugation and proteosomal degradation of PDE4D are controlled by a cullin 1-containing E(3) ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3beta (GSK3beta) in a phosphodegron motif. Our findings identify a novel signaling process governing G-protein-coupled cAMP signal transduction-opposing actions of the phosphatase calcineurin and the CK1/GSK3beta protein kinases on the phosphodegron-dependent degradation of PDE4D. This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients.
Molecular and cellular biology 09/2010; 30(18):4379-90. · 6.06 Impact Factor
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ABSTRACT: Hydrogen sulfide (H(2)S) is an endogenous signaling molecule with potent cytoprotective effects. The present study evaluated the therapeutic potential of H(2)S in murine models of heart failure.
Heart failure was induced by subjecting mice either to permanent ligation of the left coronary artery for 4 weeks or to 60 minutes of left coronary artery occlusion followed by reperfusion for 4 weeks. Transgenic mice with cardiac-restricted overexpression of the H(2)S-generating enzyme cystathione gamma-lyase (alphaMHC-CGL-Tg(+)) displayed a clear protection against left ventricular structural and functional impairment as assessed by echocardiography in response to ischemia-induced heart failure, as well as improved survival in response to permanent myocardial ischemia. Exogenous H(2)S therapy (Na(2)S; 100 microg/kg) administered at the time of reperfusion (intracardiac) and then daily (intravenous) for the first 7 days after myocardial ischemia also protected against the structural and functional deterioration of the left ventricle by attenuating oxidative stress and mitochondrial dysfunction. Additional experiments aimed at elucidating some of the protective mechanisms of H(2)S therapy found that 7 days of H(2)S therapy increased the phosphorylation of Akt and increased the nuclear localization of 2 transcription factors, nuclear respiratory factor 1 and nuclear factor-E2-related factor (Nrf2), that are involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis.
The results of the present study suggest that either the administration of exogenous H(2)S or the modulation of endogenous H(2)S production may be of therapeutic benefit in the treatment of ischemia-induced heart failure.
Circulation 07/2010; 122(1):11-9. · 14.74 Impact Factor
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ABSTRACT: The anion nitrite is an oxidative breakdown product of nitric oxide (NO) that has traditionally been viewed as a diagnostic marker of NO formation in biological systems. In this regard, nitrite has long been considered an inert oxidation product of NO metabolism. More recently, this view has changed with the discovery that nitrite represents a physiologically relevant storage reservoir of NO in blood and tissues that can readily be reduced to NO under pathological conditions. This has sparked a renewed interest in the biological role of nitrite and has led to an extensive amount of work investigating its therapeutic potential. As a result, nitrite therapy has now been shown to be cytoprotective in numerous animal models of disease. Given the very robust preclinical data regarding the cytoprotective effects of nitrite therapy it is very logical to consider the clinical translation of nitrite-based therapies. This article will review some of this preclinical data and will discuss the potential use of nitrite therapy as a therapeutic agent for the treatment of cardiovascular diseases including: ischemia-reperfusion injury (i.e. acute myocardial infarction and stroke), hypertension, angiogenesis, and as an adjunctive therapy for transplantation of various organs (i.e. liver and lung).
Nitric Oxide 11/2009; 22(2):91-7. · 3.55 Impact Factor
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ABSTRACT: Hydrogen sulfide (H(2)S) is a colorless, water soluble, flammable gas that has the characteristic smell of rotten eggs. Like other members of the gasotransmitter family (nitric oxide and carbon monoxide), H(2)S has traditionally been considered to be a highly toxic gas and environmental hazard. However, much like for nitric oxide and carbon monoxide, the initial negative perception of H(2)S has evolved with the discovery that H(2)S is produced enzymatically in mammals under normal conditions. As a result of this discovery, there has been a great deal of work to elucidate the physiological role of H(2)S. H(2)S is now recognized to be cytoprotective in various models of cellular injury. Specifically, it has been demonstrated that the acute administration of H(2)S, either prior to ischemia or at reperfusion, significantly ameliorates in vitro or in vivo myocardial and hepatic ischemia-reperfusion injury. These studies have also demonstrated a cardioprotective role for endogenous H(2)S. This review article summarizes the current body of evidence demonstrating the cytoprotective effects of H(2)S with an emphasis on the cardioprotective effects. This review also provides a detailed description of the current signaling mechanisms shown to be responsible for these cardioprotective actions.
Antioxidants & Redox Signaling 09/2009; 12(10):1203-17. · 8.20 Impact Factor
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ABSTRACT: The recent emergence of hydrogen sulfide (H(2)S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms.
The present study evaluated potential mechanisms of H(2)S-mediated cardioprotection using an in vivo model of pharmacological preconditioning.
H(2)S (100 microg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H(2)S. Initial studies revealed that H(2)S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H(2)S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Cepsilon and STAT-3. During the late preconditioning period, H(2)S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad.
These results reveal that the cardioprotective effects of H(2)S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.
Circulation Research 08/2009; 105(4):365-74. · 9.49 Impact Factor
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ABSTRACT: A comprehensive number of epidemiological and animal studies suggest that prenatal and early life events are important determinants for disorders later in life. Among them, prenatal stress (i.e. stress experienced by the pregnant mother with impact on the fetal ontogeny) has clear programming effects on the cardiovascular system. A fetus developing in adverse conditions becomes an adult who is susceptible to disease, which may include hypertension, insulin resistance, altered blood lipid levels and cardiovascular disease. Recent evidence demonstrates that maternal programming can occur in the absence of other adverse environmental factors. Obesity, which is becoming a problem of large proportions in Western countries, is a possible cause of programming. With over 30% of the population of the USA currently obese, many mothers suffer from obesity during their child-bearing years (in fact, these conditions are often aggravated during pregnancy). One of the targets of programming is the cardiovascular system, and reported consequences include hypertension, endothelial dysfunction and vascular abnormalities. The overall goal of our study was to investigate the susceptibility of the heart to ischaemia-reperfusion in an animal model of maternal obesity. Our data demonstrate that normal (non-mutant) offspring from obese agouti mouse dams had an increased susceptibility to ischaemia-reperfusion injury. These data may provide insights into the long-term cardiovascular consequences of programming.
Experimental physiology 05/2009; 94(7):805-14. · 3.17 Impact Factor
