GG MEDIATED PATHWAYS AND VENTRICULAR HYPE
Myocardial hypertrophy is an adaptive response to pressure overload and represents an initial step in the pathogenesis of many cardiac diseases which ultimately progress to ventricular failure. Biochemical mediators which initiate the hypertrophic response are poorly understood. In vitro studies with neonatal myocytes have demonstrated that activation of membrane-bound receptors which couple to the heterotrimeric guanine nucleotide-binding (G) protein, Gq, results in cellular hypertrophy. Stimulation of the alpha1 adrenergic receptor (AR) is the most studied Gq- mediated pathway which induces both myocyte hypertrophy in vitro and nuclear transcription factors associated with hypertrophy. The purpose of this study is to characterize the role of myocardial Gq-mediated pathways in ventricular hypertrophy using an in vivo model. Several lines of transgenic mice will be created with cardiac-specific expression of either the third intracellular loop region of the alpha1B-AR o the carboxyl terminus of the Gq-alpha subunit. These two peptides have been shown to inhibit phospholipase C signaling via Gq in mammalian cells in culture. Morphological changes will be determined in transgenic animals compared to controls using heart to body weight ratios and determination of ventricular myocyte cross-sectional area. Biochemical mediators of Gq- activation will also be studied. Transgenic and control mice will then undergo pulmonary artery (PA) banding which produces right ventricular pressure overload and subsequent hypertrophy. Biochemical, morphological, and histological characterization of the myocardium will be performed at various times after PA banding for both groups. This will define the importance of Gq signaling in the initiation of the hypertrophic response.