The sympathetic nervous system, catecholamines, and adrenergic receptors (ARs) have a primary role in cardiac regulation in health and disease. Past work has focused on beta-ARs, and alpha-1-ARs have been relatively neglected. However, basic studies and clinical trials, involving loss and gain of function by drugs and genetics, all now suggest the novel idea that alpha-1-ARs on cardiac myocytes have essential adaptive and beneficial, long term """"""""trophic"""""""" roles. This new insight provides important rationale to explore fundamental mechanisms of cardiac myocyte alpha-1-ARs. Alpha-1-ARs have 3 subtypes, A, B, and D, with the A and B in myocytes. To test physiological roles in vivo, this lab made and characterized a double knockout (KO) of the A and B subtypes. The alpha-1-ABKO suggested that the A and B subtypes were required for normal myocyte developmental growth, fetal gene induction with pressure overload, and protection from apoptosis. However, the respective individual roles of the A and B subtypes in myocytes are unknown, and are a prerequisite to understand alpha-1AR mechanisms. Thus, this continuation will test the hypothesis that the A and B subtypes have distinct physiological trophic roles in cardiac myocytes, with the B essential for myocyte developmental growth, and the A required for myocyte fetal gene and myosin induction and resistance to apoptosis. These distinct physiological end- points are proposed to result via activation of distinct myocyte signaling. The primary approach will be to test congenic KO mice with a single subtype missing, to ask if the subtype is required for a physiological role, or KO mice with a single subtype present, to test if a subtype is sufficient. Transgenic rescue in the KO background will be used to test a cardiac myocyte-specific effect of each subtype.
AIM I will test systemic effects by rescue, AIM II will test the role in development of the B in growth, independent of sex hormones, and the A in myosin, AIM III will test the role of the A in fetal genes, myosin, and apoptosis with pressure overload, and AIM IV will test for distinct signaling in isolated myocytes. Discovery of the physiological trophic roles in vivo of the cardiac myocyte alpha-1A and alpha-IB subtypes is the necessary foundation for future basic and clinical research in alpha-1-ARs.
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