This application addresses one of the most fundamental aspects of the effect of aging on cardiovascular function, cardiac aging (CA), and congestive heart failure (CHF). Myocardial aging leads to a progressive decline in cardiac function and -adrenergic reserve, which increases the risk of CHF and cardiac morbidity. However, the precise mechanism is unclear. This grant investigates the role and mechanism of the signaling pathway mediated by 3-adrenergic receptors (ARs) in CA. This pathway has negative effects on cardiac function, but has received limited attention in age-associated cardiac dysfunction. Our recent observations have shown that aging up-regulates cardiac 3-ARs with enhanced 3-AR-mediated negative modulations on cardiac function, [Ca2+]i regulation and the effectiveness of -adrenergic signaling. Chronic 3-AR stimulation triggers up-regulation of cardiac inducible nitric oxide synthase (iNOS) and its uncoupling. Oxidant stress from iNOS uncoupling further aggravates cardiac dysfunction. These aging-induced alterations were prevented in 3-AR knockout (3KO) aged mice and were reversed through treatment with a 3-antagonist (ANT) in wild- type (WT) aged mice, suggesting that alteration of cardiac 3-AR may be a critical element in the development of CA. We will test the Central Hypothesis that up-regulation of cardiac 3-AR signaling, as a consequence of aging-induced sympathetic overdrive (with elevated catecholamine levels), not only contributes to, but is an important cause of CA. Thus, antagonizing 3-AR with a selective 3-ANT would be effective on the prevention and treatment of CA, leading to a normalization of 3-AR expression and Ca2+ cycling/handling of cardiomyocytes, while contributing to the preservation of 1-and 2-ARs and ventricular arterial de-stiffening in the elderly. Studies will be conducted in age-matched and sex-matched SPF young and aged mice of control wild-type (WT), 3KO, 3TG/3KO and aged WT with and without chronic 3-ANT treatment.
Three specific aims are proposed to study intact animals, isolated cardiomyocytes, and molecular mechanisms. Using an integrative and multidisciplinary approach, serial and simultaneous measurements of LV structure alterations, LV and myocyte as well as vascular functional performance, cardiac calcium handling, gene expression, redox state, NOS coupling status, and neurohormonal activation in these animals will characterize the alterations of 3-AR-mediated functional responses with related molecular and cellular signal transductions of CA and define the role and mechanism of 3-ANT therapy in CA. This work will unravel aging-induced alterations at multiple levels (heart, cellular, sub-cellular, and molecular) and glean crucial insights concerning how the balance of 3- , 1-, and 2-ARs and the altered 3-AR-mediated nitric oxide signaling affects cardiovascular performance in aging. This is a highly innovative proposal, and the outcomes will have a high impact, enhancing our understanding of the pivotal mechanisms of CA and CHF and may lead to new therapeutic targets for this important problem. These studies may also provide the rationale for the study of 3-blockers in human CA.
This study addresses the important cardiovascular problem of progressively declining left ventricular systolic and diastolic functional performance associated with desensitization of the beta-adrenergic receptor system in aging hearts. The successful outcome of the proposed studies will unravel aging-induced cellular and molecular alterations in cardiomyocytes and provide crucial information concerning cardiac beta3-adrenergic signaling in cardiac aging, which will lead to new therapeutic targets for this important problem.
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