GG MEDIATED PATHWAYS AND VENTRICULAR HYPE

心肌肥大是对压力超负荷的适应性反应， 是许多心脏疾病发病机制的初始步骤 最终导致心室衰竭生化介质 引发肥大反应的机制还知之甚少体外 对新生心肌细胞的研究表明， 与异源三聚体鸟嘌呤偶联的膜结合受体 核苷酸结合（G）蛋白Gq导致细胞肥大。 α 1肾上腺素能受体（AR）的刺激是研究最多的Gq- 介导的途径，在体外诱导肌细胞肥大， 与肥大相关的核转录因子。的目的 本研究旨在描述心肌Gq介导通路的作用， 在心室肥大中的作用。几行 将产生心脏特异性表达 α 1B-AR的第三胞内环区或羧基 Gq-α亚基的末端。这两种肽已被证明 在培养的哺乳动物细胞中通过Gq抑制磷脂酶C信号传导。 将在转基因动物中测定形态学变化， 使用心脏与体重比进行对照， 心室肌细胞横截面积。Gq的生化介质- 还将研究激活。 然后转基因小鼠和对照小鼠 进行肺动脉（PA）结扎， 压力超负荷和随后的肥大。 生物化学，形态学， 心肌的组织学表征将在 两组PA显带后不同时间。这将定义 Gq信号在肥大反应起始中的重要性。

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.