CaMKII mediates vascular smooth cell hypertrophy and hypertension

CaMKII介导血管平滑细胞肥大和高血压

• 批准号: 8262622
• 负责人: Isabella Maria Grumbach
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262622
• 关键词: Address; Affect; Angiotensin II; Animal Model; Animals; Antihypertensive Agents; Aorta; Arteries; Atherosclerosis; Blood Pressure; Blood Vessels; Calcium; Calmodulin; Calmodulin 1; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Chronic; Clinical Trials; Collaborations; Data; Development; Disease; Environment; Funding; Goals; HDAC4 gene; Hand; Healthcare; Heart failure; Hypertension; Hypertrophy; In Vitro; Knowledge; Laboratories; Medial; Mediating; Molecular; Molecular Biology Techniques; Morbidity - disease rate; Muscle function; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Physiology; Polypharmacy; Protein Chemistry; Protein-Serine-Threonine Kinases; Reporting; Research; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Specificity; Stroke; Techniques; Testing; Therapeutic Agents; Vascular Smooth Muscle; Vascular remodeling; Vasoconstrictor Agents; Vasomotor; Veterans; Work; base; constriction; derepression; fighting; hypertension control; hypertension treatment; in vivo; in vivo Model; inhibitor/antagonist; intercellular communication; mortality; mouse model; muscle hypertrophy; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pressure; prevent; programs; research study; response; treatment strategy; vasoconstriction

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.

描述（由申请人提供）： 2000 年，退伍军人事务部花费了超过 1.5 亿美元用于治疗高血压。然而，尽管采用了多种药物治疗，但只有 50% 的退伍军人经常达到血压目标。显然需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，然而，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。具体来说，我们的初步研究表明，(1) CaMKII 抑制可减少体内和体外血管平滑肌肥大，(2) 主动脉和阻力血管中的血管收缩反应。 (3) 全身性 CaMKII 阻断可降低 Ang-II 高血压。 基于这些发现，我们假设（1）体内 VSM 中的 CaMKII 抑制可减少高血压中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 去抑制诱导 VSM 细胞肥大。 我们将结合多种互补的最先进技术（分子生物学、蛋白质化学、细胞信号传导和生理学、动物生理学）来剖析 VSM 中 CaMKII 信号传导的组成部分以及 CaMKII 对体内高血压和中膜肥厚的影响。所有这些技术都在我们的实验室或我们合作者的实验室中。 公共卫生相关性： 对退伍军人医疗保健的潜在影响 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 万退伍军人接受了高血压治疗。2000 年，退伍军人管理局仅在抗高血压药物上就花费了约 1.5 亿美元。尽管做出了这些努力，但接受高血压治疗的退伍军人中有 50% 没有达到血压治疗目标。 仍然迫切需要开发治疗高血压的新概念。该提案旨在研究多功能钙/钙调蛋白依赖性激酶 II (CaMKII) 在高血压、血管舒缩反应和血管平滑肌肥大中的作用。 CaMKII 的抑制可能代表一种治疗高血压和预防血管重塑的新方法。