Ion Channel Regulation Coronary Smooth Muscle Phenotype

离子通道调节冠状动脉平滑肌表型

• 批准号: 7140016
• 负责人: DOUGLAS K BOWLES
• 金额: $ 27.3万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140016
• 关键词: atherosclerosis; calcium channel; calcium flux; cardiovascular disorder prevention; coronary disorder; dietary lipid; disease /disorder model; exercise; gene expression; hyperlipidemia; microspectrophotometry; miniature swine; mitogens; nitric oxide; nitric oxide synthase; nutrition related tag; phenotype; potassium channel; small interfering RNA; transcription factor; vascular endothelium; vascular smooth muscle; voltage gated channel; western blottings

It is becoming increasingly evident that calcium influx in vascular smooth muscle is a strong modulator of smooth muscle (SM) gene regulation and phenotype via activation of calcium-dependent transcription factors. We provide evidence that L-type calcium influx is necessary for the constitutive expression of smooth muscle-specific differentiation markers (SMX: e.g. SMMHC, SMaA) and that exercise can increase L-type calcium channel function in coronary smooth muscle (CSM). The general aim of this proposal is to determine the mechanism(s) by which exercise training limits CSM phenotype switching during atherosclerosis. The overall hypothesis is that calcium influx via L-type, voltage-gated calcium channels (L-VGCC) stabilizes CSM in a differentiated, contractile phenotype. Conversely, dedifferentiation and proliferation are stimulated by upregulation of intermediate-conductance K channels (IK) and store-operated calcium channels (SOC). Exercise training prevents CSM phenotypic switching by maintaining L-VGCC activity and subsequent SM-specific, calcium-dependent gene expression. The Specific Aims are:1) Determine the effect of atherosclerosis on CSM ion channel functional expression, 2) Determine the effect of atherosclerosis on intracellular calicum regulation by membrane potential, 3) Determine the effect of L-type VGCC- versus IK/SOC-mediated calcium influx on calcium-dependent transcription factors and SMX and 4) Determine whether exercise training can prevent the loss of L-type VGCC-mediated SMX. Early and advanced models of atherosclerosis will be produced in swine by dietary high-fat, high-cholesterol (HFC) or balloon injury. Both in vitro and in vivo measures of CSM phenotype will be determined using molecular, cellular and in vivo coronary angiography techniques. The proposed research will provide the first mechanistic link between coronary ion channel activity and CSM phenotype switching. Furthermore, it will provide the first mechanistic examination of the role of CSM in the cardioprotective effect of exercise.

越来越明显的是，血管平滑肌中的钙流入是血管平滑肌的强大调节剂。 通过激活钙依赖性转录来调节平滑肌 (SM) 基因和表型 因素。我们提供的证据表明 L 型钙内流对于 的组成型表达是必需的 平滑肌特异性分化标记物（SMX：例如 SMMHC、SMaA）并且运动可以增加 冠状动脉平滑肌 (CSM) 中的 L 型钙通道功能。该提案的总体目标是 确定运动训练限制 CSM 表型转换的机制 动脉粥样硬化。总体假设是钙通过 L 型电压门控钙通道 (L-VGCC) 流入 将 CSM 稳定在分化的收缩表型中。相反，去分化和 中电导 K 通道 (IK) 和库操作的上调可刺激增殖 钙通道（SOC）。运动训练通过维持 L-VGCC 来防止 CSM 表型转换 活性和随后的 SM 特异性、钙依赖性基因表达。具体目标是：1) 确定动脉粥样硬化对CSM离子通道功能表达的影响，2)确定 动脉粥样硬化对细胞内钙通过膜电位的调节，3）确定L型的作用 VGCC-与 IK/SOC 介导的钙依赖性转录因子和 SMX 介导的钙内流和 4) 确定运动训练是否可以防止 L 型 VGCC 介导的 SMX 丢失。早期和 先进的动脉粥样硬化模型将通过饮食中的高脂肪、高胆固醇（HFC）或 气球损伤。 CSM 表型的体外和体内测量将通过分子、 细胞和体内冠状动脉造影技术。拟议的研究将提供第一个 冠状动脉离子通道活性与 CSM 表型转换之间的机制联系。此外，它将 首次对 CSM 在运动心脏保护作用中的作用进行了机械检查。