Non lipid-lowering statin effects mediated by PI3K

描述(申请人提供)：我们的研究重点是磷脂酰肌醇3-激酶(PI3K)家族蛋白在维持心血管健康和心血管疾病进展中的作用。这项研究的目的是为了更好地了解PI3K介导的3-羟基-3-甲基古氨酰基(HMG)辅酶A(CoA)还原酶抑制剂(他汀类)的细胞内信号机制和细胞后果。特定的PI3K亚型介导不同的功能。例如，在心脏中，PI3K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PI3K亚型被激活。这项提案的具体目的将检验这样一个假设，即刺激PI3K亚型或亚型导致不同的细胞信号事件对辛伐他汀的反应独立于降脂。该方法将通过使用过度表达突变的PI3K亚型的腺病毒构建物来解决辛伐他汀激活PI3K的细胞机制。将评估PI3K在钙动员、下游通路的激活或失活以及对辛伐他汀反应的胆固醇敏感基因转录中的作用。这项工作的发现将有助于理解辛伐他汀诱导的、非降脂的PI3K介导的人冠状动脉内皮细胞通路，并有助于显著改进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.