AT2 Receptors in Cardiovascular Control

描述(申请人提供)：血管紧张素II(Ang II)I型(AT1) 受体拮抗剂是最近使用的药物库中的新成员 治疗高血压和相关的心血管疾病。尽管这些 药物也会导致循环中Ang II的大幅增加， 临床试验表明，血药浓度升高没有严重副作用。 这种荷尔蒙。事实上，最近的研究表明，这种AT受体 拮抗剂诱导的血浆Ang II升高可能通过其机制发挥心脏保护作用 血管紧张素Ⅱ2型(AT2)受体介导的血管扩张作用的确，吉恩 “基因敲除”研究表明，缺乏AT2受体的突变小鼠表现出 对Ang II的基础血压和升压反应增加。我们使用了一种新的 利用体内基因转移技术“敲除”AT2R的探讨 支持这一观点。基于这一点以及AT2受体 在新生儿AT2受体的主要表达中，我们开发了 关于AT2受体在心血管中的作用的以下假说 监管。我们认为在新生大鼠中，AT2受体参与 心血管系统的正常发育，并允许它在 一生都有生理上的界限。我们还建议，这包括 AT1受体介导的升压作用的血管舒张性平衡 因此，血管紧张素转换酶II在患有AT2R的新生儿中“击倒”AT2受体--就像 允许血管收缩机制占优势，导致基础 成人的血压和升压反应。反之，则结束 AT2R-5在新生儿生命中的AT2受体的表达将允许 血管扩张机制占优势，导致升压反应减弱 在成年人身上。最后，我们提出了SHR大鼠血压可以通过 AT2受体5在新生儿生活中的表达我们将检验这些假设 使用分子、体外和体内生理学的组合 以逆转录病毒传递AT2R-AS和AT2受体为中心的方法 将正义(AT2R-S)导入幼鼠体内，对AT2受体产生最大作用。这个 具体目标如下：目标1：确定最佳条件 AT2受体功能的体外调控。目标2：定义 AT2受体在心血管系统中的生理作用 利用AT2R-AS在幼鼠体内的系统递送。目标3：调查 幼年大鼠血管紧张素转换酶受体的过度表达是否减弱 高血压的发展。这项提议在方法上是创新的，因为 它将第一次使我们能够深入分析 AT2受体处于相对正常的设置，没有生殖系操纵。我们 相信这些研究本质上是低风险的，并将对 基于基因打靶的新策略的开发，用于治疗 高血压和心血管疾病。

DESCRIPTION (provided by the applicant): Angiotensin II (Ang II) type I (AT1) receptor antagonists are the most recent addition to the arsenal of drugs used n treating hypertension and associated cardiovascular disease. Although these pharmaceutical agents also elicit large increases in circulating Ang II, clinical trials indicate no serious side effects associated with raised levels of this hormone. In fact, recent studies have suggested that this AT, receptor antagonist-induced increase in plasma Ang II may be cardioprotective via its vasodilatory actions mediated by Ang II type 2 (AT2) receptor. Indeed, gene "knockout' studies indicate that mutant mice lacking the AT2 receptor exhibit increased basal BP and pressor responses to Ang II. We have used a novel approach to "knockdown" AT2R by in vivo gene transfer technology to further support this view. Based upon this and the fact that AT2 receptors are predominant in neonatal expression of AT2 receptors, we have developed the following hypotheses concerning the roles of AT2 receptors in cardiovascular regulation. We propose that in neonatal rats AT2 receptors participate in normal development of the cardiovascular system and allow it to operate within physiological boundaries throughout life. WE further propose that this includes a vasodilatory counterbalance to the AT1 receptor-mediated pressor actions of Ang II, Thus, "knocking down" AT2 receptors in neonatal life with AT2R-AS would allow vasoconstrictor mechanisms to predominate, resulting in increased basal blood pressure (BP) and pressor responses in adults. Conversely, over expression of AT2 receptors in neonatal life with AT2R-5 would allow vasodilator mechanisms to predominate, resulting in decreased pressor responses in adults. Finally, we propose that BP can be lowered in SHR rats by over expression of AT2 receptor5 in neonatal life. We will test these hypotheses using a combination of molecular, in vitro and in vivo physiological approaches, centered around the retroviral delivery of AT2R-AS and AT2 receptor sense (AT2R-S) into young rats to elicit maximal effects on AT2 receptors. The specific aims are as follows: Aim 1: To determine the optimal conditions for modulation of AT2 receptor function in vitro. Aim 2: To define the physiological role of the AT2 receptor in the cardiovascular system by utilizing systemic delivery of AT2R-AS in the young rat. Aim 3: To investigate whether over expression of AT; receptors in young rats attenuates the development of hypertension. The proposal is innovative in its approach because it will allow, for the first time, an in depth analysis of the functions of the AT2 receptor in a relatively normal setting, without germ line manipulation. We believe that the studies are low risk in nature and will have a high impact on the development of new strategies based on gene targeting, for the treatment of hypertension and cardiovascular disease.