Vascular Smooth Muscle Hyper-contractility/Hypertension

血管平滑肌收缩过度/高血压

• 批准号: 7143490
• 负责人: MING C GONG
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143490
• 关键词: biological signal transduction; calcium flux; dietary lipid; disease /disorder model; enzyme activity; enzyme inhibitors; genetically modified animals; guanine nucleotide binding protein; hypertension; kinase inhibitor; laboratory mouse; noninsulin dependent diabetes mellitus; phosphoprotein phosphatase; phosphoproteins; phosphorylation; protein kinase C; protein structure function; serine threonine protein kinase; telemetry; tissue /cell culture; vascular smooth muscle; vasomotion

DESCRIPTION (provided by applicant): Sixteen million Americans have type II diabetes, and vascular complications are the most common causes of morbidity and mortality in diabetic patients. Abnormalities in blood vessel constriction or dilatation (vasomotion) detected in early diabetes can result in blood flow dysregulation and increased peripheral resistance, thereby contributing to diabetic complications. We and others found that db/db and high fat diet-induced type II diabetic mice are hypertensive and vascular smooth muscle tissues isolated from these animals exhibit a significantly increased contractile response to stimuli. However, the molecular mechanisms are unknown. In preliminary studies we observed that Ca2+sensitization of contractions are significantly increased in vascular smooth muscle tissues isolated from type II diabetic mice. We found that CPI-17, PKCbetall, RhoA, and ROCK, four key players of Ca2+ sensitization signaling, are significantly up-regulated/ activated in diabetic arteries. Moreover, inhibiting PKC or ROCK diminished the enhanced Ca2+ sensitization of contractions in vascular smooth muscle tissue isolated from db/db mice. Therefore, we hypothesize that in type II diabetes, activated PKCbetall and RhoA/ROCK activate CPI-17 and thereby significantly contribute to type II diabetic vascular smooth muscle hyper-contractility and hypertension. Specific aims are: (1) To test the hypothesis that activation of CPI-17 is responsible for enhanced Ca2+ sensitization and vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (2) To test the hypothesis that the activation of PKCbetall and RhoA/ROCK are required for vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (3) To test the in vivo significance of the CPI-17 in vascular smooth muscle hyper-contractility and type II diabetes-associated hypertension by using pharmacological and genetic approaches. Both in vitro and in vivo methods will be employed. Isolated small mesenteric arteries will be used to investigating isometric contractions, Ca2+ sensitization of contractions, the mRNA, protein and activities of CPI-17, RhoA/ROCK and PKC. In addition, blood pressure will be measured in mice by using radiotelemetry and carotid artery catheter. The proposed study may provide new insight into the molecular mechanisms of vascular smooth muscle dysfunction in type II diabetes and into the pathogenesis of diabetes-associated hypertension.

描述（由申请人提供）：1600万美国人患有II型糖尿病，血管并发症是糖尿病患者发病和死亡率的最常见原因。早期糖尿病中检测到的血管收缩或扩张（血管舒张症）的异常会导致血流失调和外周耐药性增加，从而导致糖尿病并发症。我们和其他人发现，从这些动物中分离出的高血压和血管平滑肌组织的DB/DB和高脂肪饮食诱导的II型糖尿病小鼠表现出对刺激的收缩反应显着增加。但是，分子机制尚不清楚。在初步研究中，我们观察到，从II型糖尿病小鼠分离的血管平滑肌组织中，CA2+收缩敏化显着增加。我们发现CPI-17，PKCBETALL，RHOA和ROCK是CA2+敏化信号传导的四个关键参与者，在糖尿病动脉中显着上调/激活。此外，抑制PKC或岩石减少了从DB/DB小鼠分离的血管平滑肌组织中收缩增强的增强。因此，我们假设在II型糖尿病中，活化的PKCBETALL和RHOA/ROCK激活CPI-17，从而显着有助于II型糖尿病血管平滑肌肌肉超额合同和高血压。具体目的是：（1）测试CPI-17的激活负责增强Ca2+敏化和血管平滑肌超缩率的假设，以及DB/DB和饮食诱导的II型糖尿病小鼠的激活。 （2）测试假说，即在DB/DB和饮食诱导的II型糖尿病小鼠中，PKCBETALL和RHOA/ROCK的激活是需要血管平滑肌超收缩性的。 （3）通过使用药理和遗传学方法来测试CPI-17在血管平滑肌超收缩和II型糖尿病相关的高血压中的体内意义。将采用体外和体内方法。分离的小肠系膜动脉将用于研究等距收缩，CA2+收缩敏化，MRNA，蛋白质和CPI-17，Rhoa/Rock和PKC的活性。另外，通过使用radiotelemetry和颈动脉导管，将在小鼠中测量血压。拟议的研究可以提供有关II型糖尿病中血管平滑肌功能障碍的分子机制以及与糖尿病相关高血压的发病机理的新见解。