Ischemic heart disease is a leading cause of heart failure (HF) in this country. Thus, elucidation of molecular mechanisms involved in the pathogenesis of contractile dysfunction in the ischemic and failing heart is critically important for advances in therapeutics. Signaling through adrenergic receptors (ARs) plays a critical role in heart function. Beta-ARs mediate the inotropic and chronotropic effects of sympathetic neurotransmission and alpha-ARs, through the actions of the G protein Gq, have been implicated in myocardial hypertrophy. Signaling through ARs can be dampened by the actions of the beta-AR kinase (BARK1), which phosphorylates receptors leading to desensitization. Myocardial ischemia, resulting from a variety of causes such as myocardial infarction (MI), is often accompanied by AR signaling abnormalities, ventricular dysfunction and hypertrophy, which can lead to HF. In a series of studies involving gene-targeted mice, the consequences of altering myocardial AR, BARK1 or Gq signaling had profound effects on cardiac contractility and hypertrophic responses. This proposal is formulated to learn whether similar effects can be demonstrated in the normal and ischemic rabbit heart after exogenous in vivo gene transfer using adenovirus vectors. The central hypothesis is that AR signaling abnormalities following MI contribute to the pathogenesis of HF and that efficient in vivomyocardial transfer of genes encoding specific AR, G protein and BARK1 signaling components will improve biochemical and physiological cardiac function of the infarcted heart including altering the hypertrophic response and the transition to HF.
Specific Aims are: Test the validity of a gene transfer approach to improving heart function in ischemic heart disease by studying the in vivobiochemical and physiologic effects of delivered AR-transgenes to the infarcted rabbit heart. [2] To investigate the role of Gq in ventricular hypertrophy by adenoviral-mediated cardiac gene transfer of a peptide inhibitor of Gq-signaling. [3] To utilize intracoronary myocardial gene transfer to elucidate mechanistic in vivo signaling differences between beta1-and beta2-ARs in the heart. [4] To evaluate novel """"""""advanced"""""""" adenoviral and adeno-associated viral (AAV) vectors for their effectiveness in supporting in vivo myocardial gene delivery.
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