Preliminary data from our laboratory revealed that in CHF, beta3-adrenergic receptor (AR) stimulation-induced cardiac depression on the normal myocardium is amplified, thus suggesting a direct adverse functional consequence of beta3-ARs activation in CHF. The purpose of this grant is to 1) characterize alterations of a3-AR-mediated functional responses of left ventricle (LV) before and as CHF progresses and assess the time course to establish a contributing causal role of cardiac beta3-AR in the abnormal responsiveness of catecholamine (NE) with CHF; and 2) define the cellular and molecular mechanisms of the altered beta3-AR-mediated inotropic response. We will test Hypothesis: [H1] after CHF, cardiac functional responses to exogenous and endogenous NE are altered due to (i) attenuated beta1-AR-mediated positive inotropic responses and (ii) an enhanced beta3-AR-mediated depression in LV and myocyte contraction and relaxation. (iii) During exercise with CHF, the adverse functional effects of beta3 -AR activation in CHF may be accentuated, due to increases in circulating and myocardial levels of NE, which [H2] (i) results from an increased expression of beta3-AR in CHF myocytes, (ii) accompanied with an enhanced negative modulation on [Ca2+]i regulation. (iii) These effects are linked with Gi, (iv) involving both nitric oxide (NO)-dependent and NO-independent signal transduction pathways. [H3] Chronic a1-AR blocker may attenuate, while beta3-AR antagonist may prevent LV and myocyte functional impairment and limits the progression of CHF. Studies will be conducted in chronically instrumented conscious dogs before and after pacing-induced CHF at rest and during exercise and in myocytes isolated from LV myocardium obtained by biopsy from these same animals before and after CHF. We will compare myocyte beta3-AR mRNA and protein levels; and LV and myocyte contractile, [Ca 2+]i transient, and Ca 2+ current responses to beta3- AR agonist or beta3-AR antagonist before and as CHF progresses and CHF after received three weeks of treatment with beta1-and beta3-AR blockers. The involvement of NO, and inhibitory G proteins in receptor-activated signal transduction will be evaluated by using L-NAME, and PTX. These studies will be the first detailed longitudinal study of the cardiac beta3-AR gene expression, and its functional effects at rest and during exercise before and during the progression of CHF in a clinically relevant higher mammal model of CHF. These studies are necessary to extend our knowledge regarding the cardiac beta-AR regulation and the role of these receptors in the abnormal responsiveness of catecholamine in CHF. Thus, provide valuable new insight into the mechanism of the progression of functional impairment in CHF, and may assist in specifically targeting therapy for CHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074318-04
Application #
7065190
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Buxton, Denis B
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$315,288
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Li, Tiankai; Zhang, Xiaowei; Cheng, Heng-Jie et al. (2018) Critical role of the chymase/angiotensin-(1-12) axis in modulating cardiomyocyte contractility. Int J Cardiol 264:137-144
Reyes, Santiago; Varagic, Jasmina; Ahmad, Sarfaraz et al. (2017) Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease. Curr Hypertens Rep 19:16
Zhang, Xiaowei; Cheng, Heng-Jie; Zhou, Peng et al. (2017) Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure. Int J Cardiol 236:405-412
Li, Tiankai; Cheng, Heng-Jie; Ohte, Nobuyuki et al. (2016) C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure. J Pharmacol Exp Ther 357:545-53
Shao, Qun; Cheng, Heng-Jie; Callahan, Michael F et al. (2016) Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism. Int J Cardiol 204:229-41
Ferrario, Carlos M; Ahmad, Sarfaraz; Varagic, Jasmina et al. (2016) Intracrine angiotensin II functions originate from noncanonical pathways in the human heart. Am J Physiol Heart Circ Physiol 311:H404-14
Zhou, Peng; Cheng, Che Ping; Li, Tiankai et al. (2015) Modulation of cardiac L-type Ca2+ current by angiotensin-(1-7): normal versus heart failure. Ther Adv Cardiovasc Dis 9:342-53
Masutani, Satoshi; Cheng, Heng-Jie; Morimoto, Atsushi et al. (2013) ?3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure. Am J Physiol Heart Circ Physiol 305:H923-30
Masutani, Satoshi; Cheng, Heng-Jie; Tachibana, Hideo et al. (2011) Levosimendan restores the positive force-frequency relation in heart failure. Am J Physiol Heart Circ Physiol 301:H488-96
Cheng, Heng-Jie; Grant, Kathleen A; Han, Qing-Hua et al. (2010) Up-regulation and functional effect of cardiac ?3-adrenoreceptors in alcoholic monkeys. Alcohol Clin Exp Res 34:1171-81

Showing the most recent 10 out of 16 publications