Myocardial ischemia and coronary artery disease are among the most important causes of death and disability in the U.S. Despite the intense investigation of the mechanisms of ischemic preconditioning, it has been difficult to translate that beneficial process to the clinical setting. One limitation is to discover models that actually enhance angiogenesis and collateral formation, which is the most effective way of protecting ischemic myocardium, and which is central to the current project. Therefore, we developed a swine model of repetitive episodes of low-flow coronary stenosis, which reproduces the conditions of transient and repeated ischemic episodes found in patients with ischemic heart disease, which displays collateral development through angiogenesis. Secret frizzled related protein 2 (sFRP2) was found as the most up-regulated gene uniquely in this model, indicating that this protein is potentially a novel mediator of cardiac protection conferred by chronic ischemia, as occurs in patients with coronary disease. Our preliminary data indicate that over expression of sFRP2 significantly increases angiogenesis and collateral blood flow and reduces the size of infarctions in acute myocardial ischemia. This over expression also improves the remodeling process after permanent coronary artery occlusion through two major novel mechanisms, by promoting cell survival through an uncovered endoplasmic reticulum (ER) stress response signaling, and by increasing the collateral blood flow through angiogenesis. The goal of this grant proposal is to investigate the mechanisms involved in cardiac protection by sFRP2 by using both a transgenic and knockout mouse model as well as a large animal model. We will first test our Hypothesis A that over-expression of sFRP2 in the heart will promote cardiac cell survival through a novel mechanism by enhancing the response to ER stress via the activation of ATF6 /GRP78 signaling. Importantly, we will test Hypothesis B that sFRP2 protects cardiac remodeling after chronic MI through 2 mechanisms. The first mechanism involves induction of angiogenesis/arteriogenesis, and the second mechanism involves improved cell survival through the ER stress pathway via the activation of ATF6/GRP78 signaling, Fibrosis will be a secondary and less important mechanism in cardiac remodeling. Clearly the ability to define such pathways, and thus to potentially bolster myocardial repair after injury, through a combination of arteriogenesis and protection of the myocyte through sFRP2 signaling, has enormous clinical ramifications for the treatment of both myocardial infarction and heart failure, the leading causes of death and disability in our society.

Public Health Relevance

This grant focuses on a new mechanism to prevent the adverse effects when blood flow to the heart muscle is reduced, as occurs in patients with heart attacks. The gene helps new blood vessels to grow in the heart muscle, dramatically reducing the injury from a heart attack. This study is important because of the large number of deaths in the U.S. and worldwide caused by heart attacks and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119464-01
Application #
8563199
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Schwartz, Lisa
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$452,309
Indirect Cost
$155,165
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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
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
Yan, Lin; Kudej, Raymond K; Vatner, Dorothy E et al. (2015) Myocardial ischemic protection in natural mammalian hibernation. Basic Res Cardiol 110:9
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
Vatner, Stephen F; Pachon, Ronald E; Vatner, Dorothy E (2015) Inhibition of adenylyl cyclase type 5 increases longevity and healthful aging through oxidative stress protection. Oxid Med Cell Longev 2015:250310
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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