The overall aim of this Program Project application is to identify physiological, biochemical and molecular mechanisms which are fundamental to the progression of ischemic heart disease and its progression to heart failure.
This aim will be accomplished by utilizing a combined approach of integrative and basic scientists. There are four projects and four cores, with major interactions among projects and cores. The projects range from cellular and molecular studies (Projects 1-4) to integrative whole animal physiology (Projects 1-4). This Program Project application relies heavily on the integrative approach. Even the cellular/molecular projects have a strong link to in vivo models. Project 1 utilizes a combined noel approach to determining the alteration in genes and proteins in stunned myocardium. Whereas most other studies in this field employ rodent models, one unique feature of this project is the use of the large mammalian model. Genomics elated to cell survival, Ca2+ regulation, sarcomeric proteins, and previously undescribed genes will be examined. Project 2 represents a continuation of the work in Dr. S. Vatner's laboratory using four different models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of short-term, chronic and true hibernation. The first is a model of short-term hibernation, 90-minute coronary stenosis with 4 days reperfusion. The second is a model of hibernating myocardium that will be derived from repetitive bouts of stunning using the model of 90- minute coronary and 12 hour reperfusion. The third involves another model of hibernating myocardium, which is induced in pigs with chronic ameroid constriction on a coronary artery. The fourth model is one of true hibernation in hibernating woodchucks. As related to Project 2, two novel aspects of myocardial metabolism will be investigated using NMR spectroscopy focusing on the role of nitric oxide in mediating a potential beneficial effect on metabolism during the effect of myocardial ischemia, and reperfusion. Project 3 is directed at examining cellular and molecular signaling mechanisms mediating apoptosis. In Project 3, the predominant animal models are murine, although studies in pigs will be carried out as well. Project 4 is another project that also uses large animal models, similar to Project 2, i.e., the pig, but concentrates on the cellular mechanisms of abnormalities in electrophysiological function and arrhythmias. There are several novel features of this projects as well. These studies represent the first model of myocardial stunning with parallel experiments of mechanical and electrophysiological function in isolated myocytes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL069020-03S1
Application #
6833833
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liang, Isabella Y
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$32,081
Indirect Cost
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
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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