The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of this Program Project application is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing a combined approach by integrative and basic scientists. There are 4 projects and 5 cores, with major interactions among projects and cores. All the projects include cellular and molecular studies as well as integrative whole animal physiology. All Projects use all the Cores, which is the glue that binds the Projects and provides the synergy characteristic of a Program Project. One unique aspect of this Program Project is the use of the large mammalian model, which is central to Projects 1 and 2. Project 1, """"""""Effects of Cardiac Denervation on Ischemic Protection"""""""", involves the study of the mechanisms of cardiac protection in the second window of ischemic protection in chronically instrumented conscious swine. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. Project 2, """"""""Molecular Mechanisms in Chronically Stunned Myocardium"""""""", parallels Project 1 in that it also uses the conscious, chronically instrumented swine model, but focuses on the chronic, repetitive stunning model developed in this project in the last funding period. This model recapitulates many of the features of hibernating myocardium in patients with chronic coronary artery disease, and also exhibits myocardial protection, potentially through a third window of protection. Project 3, """"""""Cell Death Promoting Mechanisms of Mst 1"""""""", also involves the study of cell survival and cell death with special emphasis on the molecule Mst 1, mammalian sterile kinase. This project is based on findings during the current funding period that Mst 1, belonging to a recently identified evolutionary conserved protein kinase cascade activated by myocardial ischemia, has unexpected and diverse functions not limited to pro-apoptosis but which contributes to cardiac dysfunction. Project 4, """"""""Survival Role of H11 Kinase during Myocardial Ischemia"""""""", is a new project which focuses on cardioprotection mechanisms invoked by H11 kinase. This project is based on work completed during the initial funding period, where one of the novel molecular mechanisms involved in myocardial stunning and hibernation discovered was H11 kinase, a molecule not previously studied in the heart, and found to afford powerful protection against myocardial ischemia. The Program Project approach is exemplified by the interactions among Projects and Cores, which strengthens each individual project and is designed to improve our understanding and delineate new therapies for patients with coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL069020-11S1
Application #
8774406
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2015-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$79,500
Indirect Cost
$29,500
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
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
Ikeda, Yoshiyuki; Shirakabe, Akihiro; Brady, Christopher et al. (2015) Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. J Mol Cell Cardiol 78:116-22
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

Showing the most recent 10 out of 194 publications