The most common form of heart disease is myocardial ischemia, which is characterized by an insufficientsupply 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 the Projectis to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which willbe accomplished by utilizing an integrative approach including cellular and molecular studies as well asintegrative whole animal physiology. Project 1 involves the study of the mechanisms of cardiac protection inthe second window of ischemic protection (SWOP) in chronically instrumented conscious swine. One uniqueaspect of this Project is the use of the large mammalian model, which resembles pathophysiology in humansmore closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large toprovide measurements of regional function, blood flow, biochemistry, molecular biology and pathology fromthe same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. The project isbased, in part, on the novel observation that either regional cardiac denervation or adrenergic receptorblockade abrogates the second window of protection. There are three major hypotheses: A)SWOP iscritically dependent on the sympathetic nervous system; B)Regional cardiac denervation alters SWOP in theremote, non-ischemic zone; C)SWOP results in enhanced long chain fatty acid (LCFA) oxidation duringischemia, potentially due to AMP kinase elevation, an effect which is abolished following SWOP in consciouspigs with regional cardiac denervation. Project 1 is tied closely to the other projects and cores, as well as tothe major themes of the Program Project, which are: 1)Mechanisms of myocardial ischemia and reperfusion;2)Molecular signaling; 3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascularresearch. This project is also linked closely to Project 2, which also studies the chronically instrumentedswine model, but in Project 2 the model is one of repetitive stunning (myocardial hibernation). Indeed,several of the aims are shared by Projects 1 and 2, since the two projects will address several of the samequestions in the two different models. Project 1 interacts with Project 3 in terms of molecular signaling andmechanisms of apoptosis, and with Project 4 particularly related to H11 kinase, which will be administered topigs with regional cardiac denervation, to determine if H11 kinase can restore protection after cardiacdenervation. Project 1 also utilizes all of the Cores.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL069020-06
Application #
7297790
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
6
Fiscal Year
2006
Total Cost
$294,665
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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
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
Zhao, Xin; Balaji, Poornima; Pachon, Ronald et al. (2015) Overexpression of Cardiomyocyte ?1A-Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling. Arterioscler Thromb Vasc Biol 35:2451-9
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
Vatner, Dorothy E; Yan, Lin; Lai, Lo et al. (2015) Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. Aging Cell 14:1075-84
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

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