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Hypoxia Inducible Factor-1 Interacts with Cyclic GMP Signaling in Protecting against Hypertrophy, Stunning and Nitrate Tolerance in the Isolated Cardiac Myocytes

by
Tao Tan
MD and MS, 2003
Beijing University of Chinese Medicine

Thesis Advisor: Harvey R. Weiss, PhD

Graduate Program of Physiology and Integrative Biology

School of Public Health/Research Building
Conference Room 258

Thursday, July 16, 2009
2:00 pm


Abstract

Heart disease is the number one health problem for both women and men in the United States. cGMP (Cyclic guanosine monophosphate) signaling is protective to the cardiovascular system but downregulated during myocardial stunning and cardiac hypertrophy. Hypoxia inducible factor (HIF-1) is recognized as a global regulator of O2 homeostasis and confers protection against cardiac ischemia. The interaction of HIF-1 and cGMP signaling is not well studied. We hypothesized that: HIF-1 could protect cardiomyocytes during stress, and these actions may be through interaction with cGMP signaling, especially through protection of PKG (cyclic GMP dependent protein kinase). Three experimental models were established: transverse aortic constriction induced pressure-overload cardiac hypertrophy, simulated ischemia-reperfusion (stunning), and chronic nitroglycerin patch induced nitrate tolerance. Ventricular cardiomyocytes were freshly isolated from adult mouse or rabbit hearts. In vivo upregulation of HIF-1 was induced by deferoxamine injection. Cardiomyocyte contraction was measured at baseline and after BNP (brain natriuretic peptide), CNP (C-type natriuretic peptide) or SNAP (S-nitroso-N-acetyl-penicillamine, a nitric oxide donor) at low and high doses, followed by KT5823 (a selective PKG inhibitor). Biochemical and molecular assays were performed to assess whether this was related to changes in either PKG protein level or activity. We found that the cGMP signaling was downregulated, represented as blunted functional effects of natriuretic peptides and nitric oxide under hypertrophy, stunning and nitrate tolerance conditions. But these compromised actions of cGMP signaling could be reversed by upregulation of HIF-1. For example, in the nonhypertrophic heart, under control conditions, high dose BNP reduced myocyte shortening by 24%, while KT5823 partially restored function. Deferoxamine treated control myocytes responded similarly. For the myocytes from hypertrophied heart, BNP had no significant effects on function. Deferoxamine restored the effects of BNP (-22%) in hypertrophic cardiac myocytes; KT5823 partially reversed this effect. Additionally, deferoxamine maintained PKG expression levels and activity in hypertrophied heart. Similarly, in the stunned rabbit myocytes, blunted effects of BNP and SNAP were also observed, and could be restored by HIF-1 upregulation through preserving the activity of PKG. Upregulation of HIF-1 also eliminated the nitrate tolerance induced by nitroglycerin patch, but through a PKG independent pathway.


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