Alpha-1-adrenergic receptors (alpha-1-ARs) in cardiac muscle are the focus of this work. These catecholamine receptors have several potentially beneficial """"""""trophic"""""""" effects in the heart, including development, hypertrophy, and preconditioning. Thus. alpha-1-ARs might be therapeutic targets in the abnormal or failing heart, and testing that idea is a major long range goal. The effects of alpha-1-AR activation are difficult to test precisely, because there are three cloned alpha-1-AR subtypes, named B, C, and D, and all three are present in the heart. In the heart, the alpha-1-AR subtypes are on cardiac myocytes, but not on fibroblasts, a potentially critical difference from many other cardiac receptors. The key question now is whether the different alpha-1-AR subtypes in myocytes have distinct physiological roles, or alternatively, have overlapping or even redundant functions. The alpha-1C subtype is implicated in myocyte hypertrophy by pharmacology and by unique regulation. Transcription of the alpha-1C is induced by hypertrophy stimuli, whereas transcription of the alpha-1B and the alpha-1D is repressed, suggesting a role for the alpha-1C in hypertrophy. On the other hand, the pharmacology is not definitive; and hypertrophy in the transgenic mouse heart can be induced by over-expression of a constitutively activated alpha-1B subtype. Therefore, this continuation will address the question whether the alpha-1-AR subtypes are specialized or redundant, by testing the hypothesis that the alpha-1C is a critical trophic receptor for cardiac development and hypertrophy. Three major aims are proposed.
Aim I. Knockout the alpha-1C-AR gene in mice, testing whether the alpha-1C is required for cardiac development, cardiac hypertrophy in the intact animal, and cell hypertrophy in cultured knockout myocytes.
Aim II. Analyze regulation of the alpha-1C-AR gene, testing whether the alpha-1C gene is stimulated by TEF-1 (Transcriptional Enhancer Factor-1), an activator of cardiac transcription.
Aim III. Over-express the alpha-1-AR subtypes in cardiac myocytes, testing whether the alpha-1C is specialized for induction of transcription and hypertrophy.
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