Control of Vascular Smooth Muscle Function by Insulin

胰岛素对血管平滑肌功能的控制

• 批准号: 7078024
• 负责人: Louis Ragolia
• 金额: $ 0.8万
• 依托单位: NYU WINTHROP HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-03 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078024
• 关键词: angiotensin II; angiotensin receptor; aorta; cardiovascular disorder risk; diabetes mellitus; endothelin; enzyme activity; hormone regulation /control mechanism; insulin; interleukin 1; laboratory rat; myosin light chain kinase; myosins; nitric oxide synthase; phosphatidylinositol 3 kinase; phosphoprotein phosphatase; phosphorylation; serine threonine protein kinase; tissue /cell culture; transfection; vascular smooth muscle; vasodilation; western blottings

DESCRIPTION (provided by applicant): Diabetes is associated with increased risk of cardiovascular diseases, which arise in part due to abnormalities in vascular smooth muscle (VSM) contraction resulting from an abnormal vascular tone. The overall goal of this project is to examine how insulin regulates the intracellular signal transduction pathways, which mediate relaxation in normal VSM and to identify potential pathway defects in diabetes. Contraction and relaxation of VSM is mediated primarily by phosphorylation and dephosphorylation of the regulatory myosin light chain (MLC20) by myosin light chain kinase and myosin bound phosphatase (MBP) respectively. The proposed studies will test the hypotheses that 1) insulin-induced vasorelaxation is mediated by MBP activation, and 2) cellular sensitivity and responsiveness to insulin and other vasoactive hormones are controlled by the factors which regulate the site-specific phosphorylation status of the myosin-bound subunit (MBS) of the phosphatase, MBP. Using aortic tissue, the proposed studies will examine 1) the role of MBP in insulin-mediated relaxation of VSM and to identify the mechanism whereby MBS regulates the MBP enzymatic activity. 2) Define the roles of PI3-kinase/Akt and RhoA/Rho kinase in insulin-mediated MBP activation and identify potential defects in these pathways in diabetes, and 3) Investigate potential interactions between angiotensin II, endothelin I and interleukin-1 [3/IL-6 and insulin signaling system and its impact on Rho signaling, MBS phosphorylation and MBP enzymatic activity. The functions of the key regulatory components on myosin dephosphorylation/relaxation will be elucidated by transfecting the gene of interest (activated MBS, PI3-kinase, iNOS, Akt, etc) into aortic tissue using adenovirus mediated gene transfer technique. Cumulatively, this work will lead to define the role of MBS in insulin activation of MBP, and the molecular basis of MBP regulation by insulin and potential cross-talk between insulin signaling pathways, cytokines and other vasoactive hormones. Thus, in a therapeutic context, the activation of MBP could be of value in preventing excessive contractility of VSM and thereby will have an important effect on reducing and/or preventing stroke, cardiovascular disease and renal failure in diabetes.

描述(申请人提供)：糖尿病与心血管疾病的风险增加有关，心血管疾病的部分原因是血管张力异常导致血管平滑肌(VSM)收缩异常。该项目的总体目标是研究胰岛素如何调节细胞内信号转导通路，这些信号转导通路介导正常VSM的松弛，并识别糖尿病潜在的通路缺陷。肌球蛋白轻链激酶和肌球蛋白结合磷酸酶(MBP)分别通过调节肌球蛋白轻链(MLC20)的磷酸化和去磷酸化来调节VSM的收缩和松弛。这些研究将验证以下假设：1)胰岛素诱导的血管松弛是由MBP激活介导的，2)细胞对胰岛素和其他血管活性激素的敏感性和反应性是由调节磷酸酶肌球蛋白结合亚单位(MBP)位置特异性磷酸化状态的因素控制的。利用主动脉组织，研究1)MBP在胰岛素介导的VSM松弛中的作用，并确定MBS调节MBP酶活性的机制。2)明确PI3-激酶/Akt和RhoA/Rho激酶在胰岛素介导的MBP活化中的作用，并确定这些通路在糖尿病中的潜在缺陷；3)研究血管紧张素II、内皮素I和白细胞介素1[3/IL-6]与胰岛素信号系统之间的潜在相互作用及其对Rho信号、MBS磷酸化和MBP酶活性的影响。通过腺病毒介导的基因转移技术将目的基因(激活的MBS、PI3-激酶、iNOS、Akt等)导入主动脉组织，从而阐明肌球蛋白去磷酸化/松弛的关键调控成分的功能。综上所述，这项工作将有助于明确MBS在MBP的胰岛素激活中的作用，以及胰岛素调节MBP的分子基础，以及胰岛素信号通路、细胞因子和其他血管活性激素之间潜在的串扰。因此，在治疗方面，MBP的激活可能在防止VSM过度收缩方面有价值，从而在减少和/或预防糖尿病患者的中风、心血管疾病和肾功能衰竭方面具有重要作用。