The sympathetic nervous system is critically involved in the pathogenesis of heart failure (HF). It is now currently well recognized from clinical studies that inhibiting sympathetic activity is salutary in HF. Whereas this approach is now routine clinically there are some limitations to the usefulness of this therapeutic approach of inhibiting sympathetic activity at the level of ?-adrenergic receptors (?-AR) in some patients with HF. The overall goal of this project is to explore the role of inhibiting ?-AR at the level of adenylyl cyclase (AC) and to study a potentially new therapeutic approach for HF, i.e., inhibition of type 5 adenylyl cyclase (AC5). Our overall hypothesis is that AC5 is a key enzyme mediating cardiomyopathy in response to cardiac overload and secondarily to increased ?-AR signaling or to cardiomyopathy induced by chronically enhanced ?-AR signaling in mice with overexpressed ?1-AR or ?2-AR and that inhibition of AC5 rescues the cardiomyopathy in these transgenic (Tg) mice. One might suppose that reducing AC activity will, by itself, be responsible for rescuing ?-AR cardiomyopathy. However, the main source of AC activity in the heart is AC6, and, since we have demonstrated that AC5 KO only exhibit a 25-30% reduction in AC activity, the rescue of ?2-AR Tg cardiomyopathy must involve a complex interaction of mechanisms, not simply due to the modest decrease in AC activity. The goal of this project is to determine the mechanisms underlying rescue of cardiomyopathy by inhibition of AC5, which will support the clinical use of this molecule as a novel treatment for HF. There are three major hypotheses: Hypothesis A: Inhibition of AC5 protects against cell death and rescues the cardiomyopathy induced by overexpressed ?1-AR or ?2-AR. Hypothesis B: The rescue of the ?1-AR Tg or ?2-AR Tg cardiomyopathies by inhibition of AC5 permits enhanced exercise performance which is due to (1) improved cardiac output and stroke volume, (2) improved coronary reserve, and (3) enhanced nitric oxide (NO) signaling. Hypothesis C: Resistance to oxidative stress is an important mechanism in the protection against cell death and rescue of cardiomyopathy in ?1-AR Tg x AC5 knockout (KO) or ?2-AR Tg x AC5 KO bigenic mice. The implications for Public Health are self-evident, considering that heart disease and HF are the disease processes which have the greatest impact on Public Health in the US, in terms of finances and task-force, and using similar logic, finding new therapies will be crucial to minimize the impact of these disease states on Public Health.

Public Health Relevance

The implications for Public Health are self-evident, considering that heart disease and HF are the disease processes which have the greatest impact on Public Health in the US, in terms of finances and task-force, and using similar logic, finding new therapies will be crucial to minimize the impact of these disease states on Public Health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL095888-05S1
Application #
8764797
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Wong, Renee P
Project Start
2009-03-16
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$41,351
Indirect Cost
$15,344
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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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
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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
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
Yan, Lin; Kudej, Raymond K; Vatner, Dorothy E et al. (2015) Myocardial ischemic protection in natural mammalian hibernation. Basic Res Cardiol 110:9
Yan, Lin; Vatner, Stephen F; Vatner, Dorothy E (2014) Disruption of type 5 adenylyl cyclase prevents β-adrenergic receptor cardiomyopathy: a novel approach to β-adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 307:H1521-8
Lai, Lo; Yan, Lin; Gao, Shumin et al. (2013) Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation 127:1692-701
Bravo, Claudio; Kudej, Raymond K; Yuan, Chujun et al. (2013) Metabolomic analysis of two different models of delayed preconditioning. J Mol Cell Cardiol 55:19-26

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