RGS 14 Disruption, Vascular Effects Leading to Cardioprotection

 描述(申请人提供)：G蛋白信号14调节因子(RGS14)在心脏中的作用从未被研究过，我们发现RGS14 KO小鼠通过血管生成/动脉生成保护免受急性和慢性缺血的不利影响，防止心肌重构和心力衰竭的发展。为了达到这一建议的目的，我们将检验以下假设：我们的第一个假设是，阻断RGS14是一种通过血管生成和动脉生成保护心脏免受慢性心肌缺血的新机制。我们的第二个假设是，急性和慢性缺血保护的机制涉及GIAC/cAMP和RAS介导的MEK/ERK通路的激活，从而激活一氧化氮(NO)/血管内皮生长因子(VEGF)，以及阻断氧化应激。RGS14基因敲除(KO)小鼠的一个特别新颖的特征是它能够保护急性和慢性心肌缺血，并诱导动脉生成/血管生成。第二个新特征强调了研究抑制具有多种作用的基因(如RGS14)的重要性，即它引发了这些由几个远端信号通路介导的不寻常的保护作用，这些信号通路结合在一起可能比任何一个单独的机制都更有益。

 DESCRIPTION (provided by applicant): The role of the regulator of G protein signaling 14 (RGS14) in the heart has never been studied, and we found that the RGS14 KO mice are protected from the adverse effects of acute and chronic ischemia, through angiogenesis/arteriogenesis, which protects from myocardial remodeling and development of heart failure. To accomplish the aims of this proposal, we will examine the following hypotheses: Our first hypothesis is that disruption of RGS14 is a novel mechanism to protect the heart against chronic myocardial ischemia through angiogenesis and arteriogenesis. Our second hypothesis is that the mechanism of acute and chronic ischemic protection involves Gi AC/cAMP and Ras-mediated activation of the MEK/ERK pathway and consequently nitric oxide (NO)/VEGF activation, as well as blocking oxidative stress. A particularly novel feature of the RGS14 Knockout (KO) mouse is its ability to protect against both acute and chronic myocardial ischemia and to induce arteriogenesis/angiogenesis. A second novel feature, that underlies the importance of studying inhibition of a gene with multiple effects, such as RGS14, is that it elicit these unusual protective effects mediated by several distal signaling pathways, which in their combination are likely more salutary than any one of the individual mechanisms.