Non lipid-lowering statin effects mediated by PI3K

描述（由申请人提供）：我们的研究重点是磷脂酰肌醇3-激酶（PI 3 K）蛋白家族在维持心血管健康和心血管疾病进展中的作用。本研究计划的目的是更好地了解由PI 3 K介导的3-羟基-3-甲基古他酰基（HMG）辅酶A（CoA）还原酶抑制剂（他汀类药物）的细胞内信号传导机制和细胞后果。特定的PI 3 K亚型介导不同的功能。例如，在心脏中，PI 3 K可以刺激病理和生理反应，这种明显差异的关键似乎是基于哪种PI 3 K亚型被激活。本提案中的具体目的将检验以下假设：PI 3 K亚型或亚型子集的刺激导致对辛伐他汀的不同细胞信号传导事件的响应，这些事件与降脂无关。该方法将通过使用过表达突变的PI 3 K亚型的腺病毒构建体来解决辛伐他汀激活PI 3 K的细胞机制。将评价PI 3 K在Ca 2+动员、下游途径激活或失活以及胆固醇敏感性基因转录中对辛伐他汀的响应作用。这项工作的结果将有助于了解辛伐他汀诱导的，非降脂PI 3 K介导的途径在人类冠状动脉内皮细胞和显着改善目前的他汀类药物治疗。

DESCRIPTION (provided by applicant): Our research focuses on the phosphoinositide 3-kinase (PI3K) family of proteins in the maintenance of cardiovascular health and in the progression of cardiovascular disease. The objective of this research proposal is to better understand intracellular signaling mechanisms and cellular consequences of 3-hydroxy-3-methylgultaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) mediated by PI3K. Specific PI3K isoforms mediate distinct functions. For example, in the heart, PI3K can stimulate both pathologic and physiologic responses and the key to this apparent discrepancy appears to be based upon which PI3K isoform is activated. The specific aims in this proposal will test the hypothesis that the stimulation of a PI3K isoform or subset of isoforms leads to distinct cell-signaling events in response to simvastatin that are independent of lipid-lowering. The approach will be to address the cellular mechanism of PI3K activation by simvastatin through the use of adenoviral constructs that over-express mutated PI3K isoforms. The role of PI3K in Ca2+ mobilization, activation or inactivation of downstream pathways, and cholesterol-sensitive gene transcription in response to simvastatin will be evaluated. Findings from this work will contribute to the understanding of simvastatin-induced, non lipid-lowering PI3K mediated pathways in human coronary artery endothelium and to significant improvement of current statin treatment.