EXERCISE, DIABETES, & CORONARY SMOOTH MUSCLE Ca2+

锻炼、糖尿病、

• 批准号: 6630773
• 负责人: Michael Sturek
• 金额: $ 38.93万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630773
• 关键词: atherosclerotic plaque; biological signal transduction; blood lipid; calcium flux; calcium ion; confocal scanning microscopy; coronary disorder; diabetes mellitus; dietary lipid; electrophysiology; endothelin; exercise; high performance liquid chromatography; histology; myocardium; phosphorylation; sarcolemma; swine; vasomotion; voltage /patch clamp

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the extent to which exercise training decreases coronary artery disease (CAD) after stenting in diabetes and the coronary smooth muscle (CSM) Ca signaling mechanisms involved. We propose that CAD progression in non-stented conduits and/or microvascular dysfunction may contribute to the increased mortality after coronary stenting in diabetes. We have shown that Diabetic Dyslipidemic (DD) pigs have accelerated coronary atheroma, thus making it feasible to stent natural atherosclerotic lesions, not balloon-injured healthy arteries. Overall hypothesis: exercise-induced change in Ca localization is a pivotal signal to attenuate increased growth of conduit CSM and contraction of microvascular CSM after stenting in DD. Overall experimental design: coronary stents are placed in low fat fed healthy controls (C), high fat/cholesterol fed hyperlipidemic and atherosclerotic (H), diabetic dyslipidemic and atherosclerotic (DD), and DD pigs that are aerobically exercise trained (DDX). Specific Aims are to test the hypotheses that in DD, compared to non-diabetics (H), after Iong-ter m recovery from stenting: 1) In-stent restenosis is not increased; instead, progression of CAD in non-stented cohduits and microvascular dysfunction are increased and both are prevented by exercise. Intravascular ultrasound will provide high spatial resolution of in vivo morphology and intravascular Doppler FIoWires will assess microvascular dysfunction. 2) Progression of CAD in non-stented conduits, but not microvascular dysfunction, is directly related to increased coronary endothelin and smooth muscle growth, which are prevented by exercise. Histology will determine the extent of intimal thickening and endothelin content in conduits. HPLC measures of coronary artery lipids will complement histology to determine whether DD have more cellular lesions than H. 3) Progression of CAD in non-stented conduits is directly related to increased tyrosine kinase, Can., and Kca current, which are prevented by exercise. Single cell tyrosine phosphorylation, distribution of Ca stores, and nuclear Ca (Ca/n) will be measured with confocal microscopy. Ca-dependent K currents (Kca) will be measured with patch clamp. 4) Microvascular dysfunction involves no change in Can, but is directly related to decreased Kca current, which is prevented by exercise. Functional Ca release is at the sarcolemma eliciting Kca, hyperpolarization, and relaxation in C, while Kca decreases in DD. Significance of this research is the relation of clinical and functional endpoints (Aims 1,2) to the differences in Ca localization mechanisms (Aims 3,4) of the therapeutic effects of exercise on conduit vs. microvascular CSM in diabetic dyslipidemia.

描述（由申请人提供）：该项目的长期目标是确定在糖尿病和冠状动脉平滑肌（CSM）CA信号传导机制中支架支架后，运动训练减少冠状动脉疾病（CAD）的程度。 我们建议在非置换导管和/或微血管功能障碍中的CAD进展可能有助于糖尿病冠状动脉支架后的死亡率增加。 我们已经表明，糖尿病性血脂症（DD）猪已经加速了冠状动脉粥样硬化症，因此使支架天然动脉粥样硬化病变可行，而不是遭受气球的健康动脉。 总体假设：运动引起的CA定位变化是一个关键的信号，可减弱导管CSM的增长和DD支架支架后微血管CSM的收缩。 总体实验设计：将冠状动脉支架放置在低脂喂养健康对照组（C），高脂肪/胆固醇喂养高脂症和动脉粥样硬化（H），糖尿病性血脂症和动脉粥样硬化（DD）和DD Pigs，以及经过有机运动训练（DDX）的DD猪。 具体目的是检验DD与非糖尿病（H）相比，从支架上恢复后的假设：1）内部再狭窄并未增加；取而代之的是，在非固定同胞中CAD的进展和微血管功能障碍增加，并且两者都可以通过运动来阻止。 血管内超声将提供体内形态的高空间分辨率，血管内多普勒FIOWIRES将评估微血管功能障碍。 2）非固定导管中CAD的进展，而不是微血管功能障碍，与冠状动脉内皮素和平滑肌生长直接相关，这是通过运动预防的。 组织学将确定导管中内皮素含量和内皮素含量的程度。 冠状动脉脂质的HPLC测量方法将补充组织学，以确定DD是否比H的细胞病变更多。3）非固定导管中CAD的进展与酪氨酸激酶，CAN和KCA电流的增加直接相关，这是通过运动预防的。 单细胞酪氨酸磷酸化，Ca存储的分布和核CA（CA/N）将通过共聚焦显微镜测量。 CA依赖性K电流（KCA）将用斑块夹测量。 4）微血管功能障碍涉及罐头不变，但与KCA电流降低直接相关，这是通过运动所阻止的。 功能性CA释放是在肌膜中引起的KCA，超极化和C中的松弛，而KCA在DD中的降低。 这项研究的重要性是临床和功能终点的关系（目标1,2）与糖尿病性脂肪症中的锻炼对导管对导管与微血管CSM的治疗作用的CA定位机制差异（目标3,4）的关系。