Nitric oxide (NO) has been extensively studied in the setting of ischemia-reperfusion (I/R) injury. Previous studies clearly demonstrate that the deficiency of eNOS exacerbates myocardial I/R injury whereas the overexpression of eNOS, NO donor or inhaled NO gas therapy significantly protect the myocardium. NO possesses a number of physiological properties that makes it a potent cardioprotective-signaling molecule. These include vasodilation and the inhibition of oxidative stress, platelet aggregation, leukocyte chemotaxis and apoptosis. The synthesis of NO is critically influenced by various cofactors such as tetrahydrobiopterin, flavin mononucleotide and flavin adenine dinucleotide, the presence of reduced thiols, and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), as well as, substrate and oxygen availability. Without an adequate delivery of substrate and co-factors (conditions that certainly exist in the heart during ischemia), NOS is no longer able to produce NO. Therefore, alternate means to produce NO in ischemic tissues are needed to limit I/R injury. Previous studies in our lab have shown that an acute administration of nitrite protects against myocardial I/R injury. Additionally, our preliminary data demonstrates that modest changes in dietary nitrite intake significantly alter steady-state concentrations of nitrite, nitroso modified proteins, and nitrosyl-heme products and that these biochemical changes have a profound outcome on the severity of acute myocardial infarction. Furthermore, our preliminary data suggests that the observed cardioprotection is mediated, in part, by the reduction of nitrite to NO during both the oral supplementation and ischemic periods. The objective of this proposal is to test the overall hypothesis that nitrite serves as an endogenous storage form of NO that renders cardioprotection through its ability to be converted to NO. To test this hypothesis, we have proposed the following four Specific Aims.
Specific Aim 1 will investigate the optimal therapeutic strategy needed to achieve cardioprotection in the setting of myocardial I/R by evaluating different doses and durations of nitrite supplementation.
Specific Aim 2 will begin our mechanistic studies of nitrite supplementation therapy by investigating the reduction of nitrite to NO by myoglobin.
Specific Aim 3 will investigate some of the molecular mechanisms of nitrite supplementation therapy, including the effects of nitrite on the apoptotic pathway following myocardial I/R.
Specific aim 4 will investigate the effects of oral nitrite therapy on the structure and function of mitochondria following myocardial I/R. Public Health Relevance: Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and acute myocardial infarction (i.e., heart attack) affects nearly 1.1 million people every year and is responsible for approximately 220,000 deaths per year. The proposed studies will evaluate the protective actions of a novel therapeutic agent (i.e., oral nitrite therapy) in a clinically relevant experimental model system of acute myocardial infarction. The proposed studies will significantly advance our current understanding of the mechanisms responsible for myocardial cell death during a heart attack

Public Health Relevance

Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and acute myocardial infarction (i.e., heart attack) affects nearly 1.1 million people every year and is responsible for approximately 220,000 deaths per year. The proposed studies will evaluate the protective actions of a novel therapeutic agent (i.e., oral nitrite therapy) in a clinically relevant experimental model system of acute myocardial infarction. The proposed studies will significantly advance our current understanding of the mechanisms responsible for myocardial cell death during a heart attack

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093579-04
Application #
8289582
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Wong, Renee P
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$383,625
Indirect Cost
$136,125
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Polhemus, David J; Gao, Juan; Scarborough, Amy L et al. (2016) Radiofrequency Renal Denervation Protects the Ischemic Heart via Inhibition of GRK2 and Increased Nitric Oxide Signaling. Circ Res 119:470-80
Bradley, Jessica M; Organ, Chelsea L; Lefer, David J (2016) Garlic-Derived Organic Polysulfides and Myocardial Protection. J Nutr 146:403S-409S
Organ, Chelsea L; Otsuka, Hiroyuki; Bhushan, Shashi et al. (2016) Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure. Circ Heart Fail 9:e002314
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
Islam, Kazi N; Polhemus, David J; Donnarumma, Erminia et al. (2015) Hydrogen Sulfide Levels and Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Activity Are Attenuated in the Setting of Critical Limb Ischemia (CLI). J Am Heart Assoc 4:
Polhemus, David J; Bradley, Jessica M; Islam, Kazi N et al. (2015) Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome. Am J Physiol Heart Circ Physiol 309:H82-92
Bradley, Jessica M; Islam, Kazi N; Polhemus, David J et al. (2015) Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease. Am J Physiol Heart Circ Physiol 309:H305-17
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

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