CaMKII mediates vascular smooth cell hypertrophy and hypertension

描述(由申请人提供)： 2000年，退伍军人事务部在高血压治疗上花费了超过1.5亿美元。然而，尽管服用了多种药物，但只有50%的退伍军人实现了他们的血压目标。显然，有必要开发新的治疗策略来控制高血压。多功能钙/钙调蛋白依赖性激酶II(CaMKII)在血管平滑肌(VSM)中大量表达，但其在VSM功能中的作用尚未得到深入研究。我们开发了新的、最先进的技术来研究CaMKII在体外和体外血管平滑肌中的功能。我们的初步数据表明，CaMKII是高血压的关键调节因子。具体地说，我们的初步研究表明：(1)抑制CaMKII抑制体内和体外的血管平滑肌肥大，以及(2)主动脉和阻力血管的血管收缩反应。(3)全身应用CaMKII受体阻滞剂可降低Ang-II高血压。基于这些发现，我们推测：(1)体内抑制VSM中的CaMKII可降低高血压时的血管肥大和血管收缩反应，(2)VSM细胞肥大需要CaMKII，(2)CaMKII通过HDAC4去阻抑作用诱导VSM细胞肥大。我们将结合一些互补的最新技术(分子生物学、蛋白质化学、细胞信号和生理学、动物生理学)来剖析VSM中CaMKII信号的组成以及CaMKII在体内对高血压和中膜肥大的影响。所有这些技术都在我们的实验室或我们的合作者的实验室里。 公共卫生相关性： 对退伍军人健康的潜在影响心血管疾病是美国最常见的死亡原因。高血压是动脉粥样硬化、中风和心力衰竭发生的重要危险因素。总体而言，2002年有160万退伍军人因高血压接受治疗。2000年，退伍军人管理局仅在抗高血压药物上就花费了大约1.5亿美元。尽管做出了这些努力，所有接受高血压治疗的退伍军人中有50%没有达到他们的血压治疗目标。仍然迫切需要开发新的概念来治疗高血压。本研究旨在探讨多功能钙/钙调蛋白依赖的激酶II(CaMKII)在高血压、血管舒缩反应和血管平滑肌肥大中的作用。抑制CaMKII可能是治疗高血压和预防血管重塑的新途径。

DESCRIPTION (provided by applicant): The Department of Veterans Affairs spent more than $150 million dollars on treatment of hypertension in 2000. However, only 50 % of all veterans achieve their blood pressure goals often despite polypharmacy. There is a clear need to develop new treatment strategies for controlling hypertension. The multifunctional calcium/ calmodulin-dependent kinase II (CaMKII) is abundantly expressed in vascular smooth muscle (VSM), however, its role in VSM function has not been intensively investigated. We have developed new, state of the art techniques to study CaMKII function in vascular smooth muscle in vitro and in vitro. Our preliminary data suggest CaMKII as a key regulator in hypertension. Specifically, our preliminary studies show that (1) CaMKII inhibition reduces vascular smooth muscle hypertrophy in vivo and in vitro, and (2) vasoconstrictor response in aorta and resistance blood vessels. (3) Systemic CaMKII blockade reduces Ang-II hypertension. Based on these findings, we hypothesize that (1) CaMKII inhibition in VSM in vivo decreases vascular hypertrophy and vasoconstrictor response in hypertension, (2) CaMKII is required for VSM cell hypertrophy, (2) that CaMKII induces VSM cell hypertrophy by HDAC4 derepression. We will combine a number of complementary, state of the art techniques (molecular biology, protein chemistry, cell signaling and physiology, animal physiology) to dissect the components of CaMKII signaling in VSM and the effect of CaMKII on hypertension and medial hypertrophy in vivo. All of these techniques are at hand in our laboratory or the laboratories of our collaborators. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care Cardiovascular diseases are the most frequent causes of death in the US. Hypertension is an important risk factor for the development of atherosclerosis, stroke and heart failure. Overall, 1.6 million veterans were treated for hypertension in 2002. In 2000, the VA spent an estimated 150 million dollars on antihypertensives alone. Despite these efforts, 50% of all veterans on treatment for hypertension do not reach their blood pressure treatment goals. There is still a pressing need for developing new concepts to treat hypertension. This proposal is aimed at investigating the role of the multifunctional calcium/calmodulin-dependent kinase II (CaMKII) in hypertension, vasomotor response and vascular smooth muscle hypertrophy. Inhibition of CaMKII could represent a novel approach to treating hypertension and preventing vascular remodeling.