The role of the regulator of G protein signaling 14 (RGS14) in the heart has never been studied, and we found that the RGS14 KO mice are protected from the adverse effects of acute and chronic ischemia, through angiogenesis/arteriogenesis, which protects from myocardial remodeling and development of heart failure. To accomplish the aims of this proposal, we will examine the following hypotheses: Our first hypothesis is that disruption of RGS14 is a novel mechanism to protect the heart against chronic myocardial ischemia through angiogenesis and arteriogenesis. Our second hypothesis is that the mechanism of acute and chronic ischemic protection involves Gi AC/cAMP and Ras-mediated activation of the MEK/ERK pathway and consequently nitric oxide (NO)/VEGF activation, as well as blocking oxidative stress. A particularly novel feature of the RGS14 Knockout (KO) mouse is its ability to protect against both acute and chronic myocardial ischemia and to induce arteriogenesis/angiogenesis. A second novel feature, that underlies the importance of studying inhibition of a gene with multiple effects, such as RGS14, is that it elicit these unusual protective effects mediated by several distal signaling pathways, which in their combination are likely more salutary than any one of the individual mechanisms.
Cardiovascular disease is America's leading health problem, and the leading cause of death. This application will study ischemic heart disease, the most common type of heart disease, in order to identify new treatments for this serious condition. We have identified a novel gene mechanism that protects against acute and chronic ischemia resulting in tissue death in the heart by reducing remodeling and heart failure via increasing blood flow to the ischemic heart.
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|Bravo, Claudio A; Vatner, Dorothy E; Pachon, Ronald et al. (2016) A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. J Pharmacol Exp Ther 357:331-6|
|Bravo, Claudio A; Vatner, Dorothy E; Vatner, Stephen F (2016) Response to Letter to the Editor on ""Does Vidarabine Mediate Cardioprotection via Inhibition of AC5?"". J Pharmacol Exp Ther 358:244-5|
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