CARDIAC ANGIOTENSIN--LOAD INDUCED HYPERTROPHY & FAILURE

目的是检验心脏血管紧张素At/1 受体激活是强制性的，与AT/2受体相反 对于压力超负荷性肥大的发展， 在完整的心脏中转变为衰竭。 最近的研究表明， 牵张诱导新生心肌细胞肥大反应 依赖于局部血管紧张素II和AT/1受体的释放 activation. 相反，AT/2受体激活被假定为 抑制AT/1介导的细胞生长。 我们建立了一个模型， 负荷性心室肥大伴升主动脉缩窄， 其特征是在心脏收缩期间心脏血管紧张素II激活增加， 早期适应性肥大和明确的后期过渡阶段 要失败的 我们发现慢性血管紧张素转换酶- 在该模型中的抑制使肌细胞肥大消退，提高存活率， 并防止收缩功能受损的发展， 左室收缩压持续严重升高 给未经处理的带状动物。 这些数据暗示但并不能证明 心脏AT/1受体激活是负荷性肥大的必要条件 以及体内晚期向衰竭的转变。 具体目标1： 测试AT/1受体激活是必需的假设，而 AT/2激活抑制负荷诱导的即刻肥大反应 原癌基因的诱导和蛋白质合成， 体外完整离体灌流心脏。 具体目标2将测试 假设心脏分子对慢性压力的反应 超载和后期过渡到失败的特点是， 心脏肾素-血管紧张素系统基因表达进行性增加 随着“抗生长”AT/2受体的后期平衡上调， 如通过定量RT-PCR测量的。 我们将利用比较 左心室压力超负荷，导致肥厚， 右心室附近，而不是。 具体3将测试 假设慢性AT/1受体抑制，而不是AT/2受体 抑制，逆转肌细胞肥大，提高生存率，并改变 晚期转为衰竭伴左室收缩压持续升高 压力相当于未经处理的捆绑动物。 使用现已验证的 方法，我们将定量心脏功能在体内使用系列 超声心动图和LV微压计压力测量。 具体 4将确定收缩改善的细胞基础 在慢性AT/1受体抑制中起作用。 根据初步 用荧光指示剂研究分离的肥大心肌细胞 和钙调节基因表达的测量，我们预测， 改善心肌细胞[Ca ~（2+）]/i和pH/i调节 正常化的Ca 2+调节基因表达水平。 这些集成 体内生理学、分离的心肌细胞和心脏基因的研究 表达，将决定心脏AT/1受体激活是否 强制性的负荷诱导的立即肥大反应，和晚期 在体内从肥大到衰竭的转变。 这些问题都是 是人类肥大和衰竭的生物学基础。

The objective is to test the hypothesis that cardiac angiotensin At/1 receptor activation, which is opposed by the AT/2 receptor, is mandatory for the development of pressure overload hypertrophy and the later transition to failure in the intact heart. Recent studies show that the stretch-induced hypertrophic response of neonatal myocytes in vitro depends on the local release of angiotensin II and AT/1 receptor activation. In contrast, AT/2 receptor activation is postulated to counteract AT/1-mediated cell growth. We have established a model of load-induced ventricular hypertrophy with ascending aortic banding which is characterized by increased cardiac angiotensin II activation during early adaptive hypertrophy, and a well-defined later stage of transition to failure. We have made the novel observation that chronic ACE- inhibition in this model regresses myocyte hypertrophy, improves survival, and prevents the development of impaired contractile function despite persistent severe elevation of left ventricular systolic pressure relative to untreated banded animals. These data implicate but do not prove that cardiac AT/1 receptor activation is mandatory for load-induced hypertrophy and the late transition to failure in vivo. In Specific Aim 1 we will test the hypothesis that AT/1 receptor activation is required, whereas AT/2 activation inhibits, the load-induced immediate hypertrophic response of protooncogene induction and protein synthesis that we have shown in vitro in the intact isolated perfused heart. Specific Aim 2 will test the hypothesis that the cardiac molecular response to chronic pressure overload and the late transition to failure s characterized by the progressive increased expression of cardiac renin-angiotensin system genes with late counterbalancing upregulation of the "anti-growth" AT/2 receptor as measured by quantitative RT-PCR. We will exploit comparison of the pressure overloaded left ventricle which develops hypertrophy, and the adjacent right ventricle which does not. Specific 3 will test the hypothesis that chronic AT/1 receptor inhibition, but not AT/2 receptor inhibition, regresses myocyte hypertrophy, improves survival, and modifies the late transition to failure with persistent elevation of LV systolic pressure equivalent to untreated banded animals. Using now validated methodology, we will quantitate cardiac function in vivo using serial echocardiography, and LV micromanometer pressure measurements. Specific 4 will determine the cellular basis of the improvement in contractile function in chronic AT/1 receptor inhibition. Based on preliminary studies in dissociated hypertrophied myocytes using fluorescent indicators and measurements of calcium regulatory gene expression, we predict an improvement in myocyte [Ca2+]/i and pH/i regulation in association with normalized levels of Ca2+ regulatory gene expression. These integrated studies of in vivo physiology, the isolated myocyte, and cardiac gene expression, will determine if cardiac AT/1 receptor activation is mandatory for load-induced immediate hypertrophic response, and the late transition from hypertrophy to failure in vivo. These questions are fundamental to the biology of human hypertrophy and failure.