Hydrogen sulfide (H2S) has recently been identified as a physiologically important endogenous gaseous signaling molecule with a diverse array of biological activities. H2S is produced in micromolar quantities by two endogenous enzymes, cystathionine 3lyase (CGL) and cystathionine 2 synthase (CBS) and is critical for the maintenance of cardiovascular homeostasis. H2S attenuates leukocyte adhesion, modulates mitochondrial respiration, and inhibits both apoptosis, and oxidative stress. These physiological actions are ideal for the treatment of myocardial ischemia-reperfusion (MI-R) injury. Preliminary data clearly demonstrate that physiological levels of H2S significantly ameliorate MI-R injury and preserve left ventricular function. Preliminary data also indicate that H2S therapy triggers both 'early' and 'late' myocardial preconditioning. We also demonstrate that mice with cardiac-restricted CGL overexpression exhibit significantly increased myocardial H2S bioavailability and protection against myocardial I-R injury. The central hypothesis for the proposed studies is that H2S triggers a cardioprotective signaling cascade that confers robust cardioprotection in the setting of MI-R injury. The proposed studies will evaluate the various cardioprotective signals induced by H2S therapy during both 'acute' and 'chronic' pharmacological preconditioning as well as the during acute H2S therapy at the time of reperfusion.
Specific Aim 1 : To investigate the contribution of ATP sensitive K+ channels (KATP channels) in H2S- mediated cardioprotection against myocardial ischemia-reperfusion injury. In vitro studies will evaluate the effects of H2S on KATP channel activation and mitochondrial function. In vivo Studies will be performed using gene-targeted mice with cardiac myocyte deletion of KATP (Sur 1, Kir 6.1, and Kir 6.2 subunits) treated with H2S and subjected to MI-R.
Specific Aim 2 : To investigate the role of antioxidants in H2S-mediated cardioprotection. Studies will evaluate the acute and chronic effects of H2S on Nrf-2 activation and oxidative stress during MI-R. Studies will also investigate the effects of H2S on the induction of antioxidant signaling pathways in the myocardium prior to MI-R.
Specific Aim 3 : To investigate the role of the RISK pathway in H2S-mediated cardioprotection. Studies will investigate the effects of H2S on RISK pathway (PI3K, Akt, PKC5, and Erk 1/2) activation, downstream anti-apoptotic signaling, MPTP opening, and myocardial cell death following MI-R. The proposed studies will significantly extend our current understanding of the molecular and cellular pathophysiology of MI-R injury and provide the foundation for the development of H2S therapy for the treatment of acute myocardial infarction.

Public Health Relevance

Despite numerous advances in health care; cardiovascular disease remains the numberone killer in the United States and acute myocardial infarction (i.e.; heart attack) affectsnearly 1.1 million people every year and is responsible for approximately 220;000 deathsper year in the United States. The proposed studies will evaluate the efficacy of a noveltherapeutic agent (i.e.; hydrogen sulfide) in a clinically relevant and highly translationalexperimental model system of acute myocardial infarction. Experiments will determinethe precise cellular mechanisms by which hydrogen sulfide protects the heart againstacute myocardial infarction. Additional studies will examine the effects of geneticoverexpression of a critical hydrogen sulfide generating enzyme on the severity of acutemyocardial infarction. The proposed studies will significantly advance our currentunderstanding of the mechanisms responsible for myocardial cell death during a heartattack. Information gained from these studies will help with the development of noveltherapies for the treatment of patients suffering from acute myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL092141-06
Application #
8921357
Study Section
Special Emphasis Panel (ZRG1-CVS-P (02))
Program Officer
Wong, Renee P
Project Start
2009-01-01
Project End
2014-12-31
Budget Start
2014-09-15
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$284,647
Indirect Cost
$89,683
Name
Louisiana State Univ Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Bhushan, Shashi; Kondo, Kazuhisa; Polhemus, David J et al. (2014) Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling. Circ Res 114:1281-91
Polhemus, David J; Lefer, David J (2014) Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 114:730-7
King, Adrienne L; Polhemus, David J; Bhushan, Shashi et al. (2014) Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci U S A 111:3182-7
Calvert, John W; Lefer, David J (2013) Role of *-adrenergic receptors and nitric oxide signaling in exercise-mediated cardioprotection. Physiology (Bethesda) 28:216-24
Kondo, Kazuhisa; Bhushan, Shashi; King, Adrienne L et al. (2013) HýýýS protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation 127:1116-27
Nicholson, Chad K; Lambert, Jonathan P; Chow, Chi-Wing et al. (2013) Chronic exercise downregulates myocardial myoglobin and attenuates nitrite reductase capacity during ischemia-reperfusion. J Mol Cell Cardiol 64:1-10
Polhemus, David J; Kondo, Kazuhisa; Bhushan, Shashi et al. (2013) Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail 6:1077-86
Greenway, Frank L; Predmore, Benjamin L; Flanagan, Douglas R et al. (2012) Single-dose pharmacokinetics of different oral sodium nitrite formulations in diabetes patients. Diabetes Technol Ther 14:552-60
Predmore, Benjamin L; Kondo, Kazuhisa; Bhushan, Shashi et al. (2012) The polysulfide diallyl trisulfide protects the ischemic myocardium by preservation of endogenous hydrogen sulfide and increasing nitric oxide bioavailability. Am J Physiol Heart Circ Physiol 302:H2410-8
Predmore, Benjamin Lee; Lefer, David Joseph; Gojon, Gabriel (2012) Hydrogen sulfide in biochemistry and medicine. Antioxid Redox Signal 17:119-40

Showing the most recent 10 out of 29 publications