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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Schwartz, Lisa
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Rutgers University
Anatomy/Cell Biology
Schools of Medicine
United States
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Zhang, Jie; Levy, Daniel; Oydanich, Marko et al. (2018) A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion. J Mol Cell Cardiol 121:13-15
Vatner, Dorothy E; Zhang, Jie; Oydanich, Marko et al. (2018) Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell :e12751
Zhao, Zhenghang; Kudej, Raymond K; Wen, Hairuo et al. (2018) Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck). FASEB J 32:4229-4240
Guers, John J; Gwathmey, Judith; Haddad, Georges et al. (2017) Minority investigators lack NIH funding. Science 356:1018-1019
Guers, John J; Zhang, Jie; Campbell, Sara C et al. (2017) Disruption of adenylyl cyclase type 5 mimics exercise training. Basic Res Cardiol 112:59
Zhang, Jie; Zhao, Xin; Vatner, Dorothy E et al. (2016) Extracellular Matrix Disarray as a Mechanism for Greater Abdominal Versus Thoracic Aortic Stiffness With Aging in Primates. Arterioscler Thromb Vasc Biol 36:700-6
Vatner, Stephen F (2016) Why So Few New Cardiovascular Drugs Translate to the Clinics. Circ Res 119:714-7
Jose Corbalan, J; Vatner, Dorothy E; Vatner, Stephen F (2016) Myocardial apoptosis in heart disease: does the emperor have clothes? Basic Res Cardiol 111:31
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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