Heart failure is the inability of the heart to meet hemodynamic demands and represents the end stage of various forms of cardiovascular disease. In industrialized nations, heart failure represents a major health problem that has been increasing in prevalence and incidence. It is estimated that 5.7 million people in the United States have heart failure resulting in about $37.2 billion being spent a year to cover associated health care related costs. Therefore, drug therapy designed to coincide with the standard means of care are needed to decrease the extent of injury leading to the development of heart failure. Recently, hydrogen sulfide (H2S) has been shown to be cardioprotective in various in vitro and in vivo models of cardiac injury. Although the physiological and cardioprotective effects of H2S in acute models of ischemia- reperfusion injury have previously been documented, the signaling mechanisms that mediate these effects have not been fully studied. Moreover, the signaling mechanisms that have been attributed to H2S have predominantly been studied in in vitro model systems, with very few studies actually exploring the protective effects in in vivo systems. Additionally, the cardioprotective effects of H2S in the setting of heart failure have not been investigated. For this reason, the studies proposed in this application are extremely important and timely. The overall aim of this proposal is to evaluate the signaling mechanisms responsible for the observed cardioprotective effects of H2S therapy in the setting of heart failure. To this end, the transcription factor, Nrf2, has been identified as a possible regulator of these cardioprotective effects. Therefore, the central hypothesis for the proposed studies is that H2S up-regulates endogenous antioxidants, alleviates mitochondrial dysfunction, and reduces hypertrophy in a Nrf2-dependent manner. To test this hypothesis, 3 Specific Aims have been proposed.
Specific Aim 1 will evaluate the role of Nrf2 signaling in mediating the antioxidant effects of H2S.
Specific Aim 2 will investigate if H2S suppresses apoptosis and cardiac hypertrophy via Nrf2/Trx1- dependent signaling.
Specific Aim 3 will investigate if H2S induces mitochondrial biogenesis via Nrf2- dependent signaling. The proposed studies will significantly advance our current understanding of the mechanisms responsible for the development of heart failure and will answer important questions regarding the signaling mechanism responsible for the cardioprotective effects of H2S in the setting of heart failure. Additionally, information gained from these studies will provide the foundation for the development of H2S therapy for the treatment of heart failure.

Public Health Relevance

Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and heart failure, as a direct result of cardiovascular disease, affects nearly 5.3 million people in the United States resulting in about $34.8 billion being spent a year to cover associated health care related costs. The proposed studies will evaluate the efficacy of a hydrogen sulfide releasing compound in clinically relevant and highly translational experimental model systems of heart failure. The proposed studies will significantly advance our current understanding of the mechanisms responsible for the development of heart failure and will answer important questions regarding the signaling mechanism responsible for the cardioprotective effects of hydrogen sulfide in the setting of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL098481-01
Application #
7767448
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2010-01-04
Project End
2014-11-30
Budget Start
2010-01-04
Budget End
2010-11-30
Support Year
1
Fiscal Year
2010
Total Cost
$387,500
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Shimizu, Yuuki; Polavarapu, Rohini; Eskla, Kattri-Liis et al. (2018) Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK. J Mol Cell Cardiol 116:29-40
Grisanti, Laurel A; Gumpert, Anna M; Traynham, Christopher J et al. (2016) Leukocyte-Expressed ?2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury. Circulation 134:153-67
Li, Ming; Tejada, Thor; Lambert, Jonathan P et al. (2016) Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-?. Am J Cardiovasc Dis 6:118-28
Tejada, Thor; Tan, Lin; Torres, Rebecca A et al. (2016) IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction. Proc Natl Acad Sci U S A 113:6949-54
Shimizu, Yuuki; Lambert, Jonathan P; Nicholson, Chad K et al. (2016) DJ-1 protects the heart against ischemia-reperfusion injury by regulating mitochondrial fission. J Mol Cell Cardiol 97:56-66
Shimizu, Yuuki; Nicholson, Chad K; Lambert, Jonathan P et al. (2016) Sodium Sulfide Attenuates Ischemic-Induced Heart Failure by Enhancing Proteasomal Function in an Nrf2-Dependent Manner. Circ Heart Fail 9:e002368
Barr, Larry A; Shimizu, Yuuki; Lambert, Jonathan P et al. (2015) Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress. Nitric Oxide 46:145-56
Calvert, John W (2014) Nox2 targets SERCA in response to a high fat high sugar diet. J Mol Cell Cardiol 72:228-30
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
Naqvi, Nawazish; Li, Ming; Calvert, John W et al. (2014) A proliferative burst during preadolescence establishes the final cardiomyocyte number. Cell 157:795-807

Showing the most recent 10 out of 30 publications