EXCEED THE SPACE PROVIDED. The overall hypothesis of this work is that cardiac myocyte alpha-1-adrenergic receptors (ARs) have beneficial, adaptive, protective, trophic or 'nutritional' effects in cardiac myocytes. This hypothesis is relevant clinically, since alpha-1-blockers are being used to treat hypertension and prostate disease, and might inhibit these adaptive effects. Longer range, alpha-1-activating drugs might be used to treat heart muscle disease and heart failure. It is well known that the sympathetic nervous system via catecholamines are a primary mechanism of cardiac regulation, but the focus has been on beta-ARs and acute activation of contraction. More recently, recognition of the cardiac toxicity of chronic, excessive beta-AR stimulation has led to the successful use of beta-blockers to treat heart failure. Now, however, clinical trial results are showing that excessive blocking of the sympathetic nervous system can be harmful. The clinical trials coincide with numerous animal and cell studies showing beneficial cardiac effects of alpha-1-ARs in physiological hypertrophy, preconditioning, and anti-apoptosis, supporting the overall hypothesis that alpha-1-ARs mediate chronic adaptation. In recent funding, this team developed a knockout (KO) mouse of the two main alpha-1-AR subtypes in the heart, the A and B (ABKO), to provide direct support for the adaptive and protective roles of myocyte alpha-1-ARs in development and pressure overload. The continuation of the work will test the hypothesis that one subtype, the alpha-IB, confers most of the beneficial effects, with a minor role for the A subtype, and a role in coronary arteries for the D subtype. Three main aims will address this hypothesis:
AIM I. Study alpha-1-subtypes in developmental hypertrophy in vivo, assaying heart and myocyte hypertrophy and function, beta-AR regulation, and coronary flow.
AIM II. Study alpha-1-subtypes in cultured adult myocytes, assaying apoptosis, hypertrophy, and signaling.
AIM III. Study alpha-1-subtypes in adaptation to stress/injury in vivo, using models of pressure overload (transverse aortic constriction) and drug toxicity (doxorubicin).
These Aims will be possible, and conclusions will be confident, because the team has developed unique single, double, and triple alpha-1-subtype KO lines, congenic in C57BI/6. PERFORMANCE SITE ========================================Section End===========================================
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