Improving exercise tolerance, one of the major goals of physicians treating patients with cardiovascular disease, can be achieved either by improving cardiac output and blood flow to skeletal muscle, or by improving energy metabolism in skeletal muscle, or both. However, less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. In the past, we have demonstrated that the adenylyl cyclase type 5 (AC5) knockout (KO) mouse lives one third longer than wild type and is protected against aging induced cardiomyopathy, and the development of heart failure induced by either chronic catecholamine or pressure overload stress. The current project is based on these studies and our preliminary data demonstrating that AC5 KO mice exhibit increased exercise capacity. Our overall hypothesis is that AC5 is a critical enzyme affecting stress resistance and exercise capacity. The goal of this project is to examine mechanisms involved in AC5 inhibition, which could lead to a novel approach to improve exercise performance. There are two major hypotheses: HYPOTHESIS A: AC5 inhibition permits enhanced exercise performance due to improved limb blood flow through enhanced vasodilator mechanisms or angiogenesis, whereas improved cardiac function and cardiac output are less likely mechanisms. HYPOTHESIS B: AC5 inhibition permits enhanced exercise performance due to improved mitochondrial function and/or resistance to oxidative stress and/or improved glucose utilization. The implications for Public Health are clear: improving exercise tolerance will have broad significance for aging, heart disease, most other diseases and even for the young, healthy population.

Public Health Relevance

Improving exercise tolerance, one of major goals of physicians treating patients with cardiovascular disease, can be achieved either by improving cardiac output and blood flow to skeletal muscle, or energy metabolism in skeletal muscle, or both. However, less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. The goal of this project is to examine mechanisms involved in AC5 inhibition, which could lead to a novel approach to improve exercise performance. The implications for Public Health are clear: improving exercise tolerance will have broad significance for aging, heart disease, most other diseases and even for the young, healthy population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106511-02
Application #
8323343
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Schwartz, Lisa
Project Start
2011-09-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$453,345
Indirect Cost
$139,478
Name
University of Medicine & Dentistry of NJ
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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
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
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
Zhao, Xin; Balaji, Poornima; Pachon, Ronald et al. (2015) Overexpression of Cardiomyocyte α1A-Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling. Arterioscler Thromb Vasc Biol 35:2451-9
Zhao, Zhenghang; Babu, Gopal J; Wen, Hairuo et al. (2015) Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart. Am J Physiol Heart Circ Physiol 308:H240-9
Sehgel, Nancy L; Sun, Zhe; Hong, Zhongkui et al. (2015) Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 65:370-7
Pachon, Ronald E; Scharf, Bruce A; Vatner, Dorothy E et al. (2015) Best anesthetics for assessing left ventricular systolic function by echocardiography in mice. Am J Physiol Heart Circ Physiol 308:H1525-9
Lee, Grace J; Yan, Lin; Vatner, Dorothy E et al. (2015) Mst1 inhibition rescues β1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis. Basic Res Cardiol 110:7
Ho, David; Zhao, Xin; Yan, Lin et al. (2015) Adenylyl Cyclase Type 5 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance. Diabetes 64:2636-45

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