RGS 14 Disruption, Vascular Effects Leading to Cardioprotection

 描述（由申请人提供）：从未研究过G蛋白信号传导调节因子14（RGS 14）在心脏中的作用，我们发现RGS 14 KO小鼠通过血管生成/动脉生成而免受急性和慢性缺血的不良影响，从而保护心肌重塑和心力衰竭的发展。为了实现这一提议的目的，我们将研究以下假设：我们的第一个假设是，破坏RGS 14是一种新的机制，以保护心脏免受慢性心肌缺血，通过血管生成和动脉生成。我们的第二个假设是，急性和慢性缺血保护的机制涉及Gi AC/cAMP和Ras介导的MEK/ERK途径的激活，并因此一氧化氮（NO）/VEGF激活，以及阻断氧化应激。 RGS 14敲除（KO）小鼠的一个特别新颖的特征是其保护免受急性和慢性心肌缺血以及诱导动脉生成/血管生成的能力。第二个新的特征，强调了研究具有多种效应的基因（如RGS 14）抑制的重要性，它引起了由几个远端信号通路介导的这些不寻常的保护作用，这些远端信号通路的组合可能比任何一个单独的机制更有益。

 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.