Long-term Antihypertensive Therapy by Delivery of the BK Channel Gene to VSMCs

通过将 BK 通道基因递送至 VSMC 进行长期抗高血压治疗

• 批准号: 8266340
• 负责人: Nancy J Rusch
• 金额: $ 35.89万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266340
• 关键词: Adherence; Adverse effects; American; Antihypertensive Agents; Arteries; Blood Pressure; Blood Vessels; Buffers; Calcium; Cell membrane; Cells; Chronic Kidney Failure; Dependovirus; Dilator; Disease; Environmental Risk Factor; Essential Hypertension; Gene Delivery; General Population; Genes; Goals; Heart Hypertrophy; Hypertension; Hypotension; In Vitro; Incidence; Individual; Injection of therapeutic agent; Mediating; Membrane; Molecular Biology; Mus; Organ; Overactive Bladder; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasmids; Property; Proteins; Regimen; Rest; Smooth Muscle; Smooth Muscle Myocytes; Stroke; Surface; Systemic disease; Testing; Tissues; Transduction Gene; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Viral; Virus; arteriole; base; blood pressure regulation; cell type; clinical care; cost; design; gene therapy; in vivo; interest; intravital microscopy; large-conductance calcium-activated potassium channels; mouse model; non-compliance; normotensive; overexpression; patch clamp; preclinical study; pressure; promoter; response; tool; vasoconstriction; viral gene delivery; virology; voltage

Project Summary Essential hypertension is a polygenetic disease afflicting nearly 1 billion individuals worldwide. It predisposes to cardiac hypertrophy, stroke and chronic renal failure. Of the individuals offered antihypertensive drugs, only one third achieve blood pressure control due to the high cost, side effects and noncompliance associated with the daily, multi-drug therapy that is often required. In this regard, the long-term expression of vasodilator proteins would be extremely advantageous to avoid the high cost and inconvenience associated with daily drug administration, and also to minimize the blood pressure fluctuations caused by short-acting antihypertensive drugs. Of major interest as a candidate vasodilator protein is the high-conductance, calcium- activated K+ (BK) channel that is expressed in the surface membrane of vascular smooth muscle cells (VSMCs) and other cell types. The BK channel is activated by rises in intravascular pressure, and acts as a compensatory mechanism to mediate vasodilation. Thus, we envision that using adeno-associated viral (AAV) delivery to overexpress the BK channel in arterial VSMCs, we can establish a "channel reserve" of compensatory dilator proteins that will provide long-term antihypertensive therapy. Based on this premise, this proposal explores the hypothesis that: Smooth muscle-specific delivery of the BK channel gene by adeno- associated-virus (AAV) represents a therapy for the long-term control of high blood pressure. In exciting proof- of-principle studies, we observed that AAV-mediated delivery of the BK channel gene can be preferentially targeted to the vasculature using a smooth muscle-specific promoter, and this therapy lowers blood pressure in hypertensive mice. Based on these findings, we have designed four specific aims that will: Optimize BK channel gene delivery (Aim 1), assess the antihypertensive effect of AAV delivery of BK channels in two mouse models of hypertension (Aim 2), evaluate if the transduced BK channels enhance K+ current and retain normal properties in VSMC membranes (Aim 3), and evaluate the vasodilator benefit of AAV-mediated delivery of BK channels in vitro and in vivo (Aim 4). Clearly, in order to reduce the incidence of hypertension in the general population, vascular-specific, long-term antihypertensive treatments must be introduced into clinical care. In this respect, the findings of our project suggest that using AAV-mediated delivery to target BK channels to arterial VSMCs normalizes hypertension in the established phase of the disease, suggesting a new paradigm for antihypertensive treatment that avoids the daily administration of antihypertensive drugs.

项目摘要 原发性高血压是一种多基因疾病，在全世界范围内影响着近10亿人。它会使 心脏肥大中风和慢性肾衰竭在提供抗高血压药物的个体中，只有 三分之一的人由于高成本、副作用和与之相关的不依从性而实现血压控制。 每天都需要多种药物治疗。在这方面，血管扩张剂的长期表达 蛋白质将是极其有利的，以避免与日常饮食相关的高成本和不便。 药物管理，并尽量减少短效引起的血压波动 抗高血压药作为候选血管扩张蛋白的主要兴趣是高电导，钙- 在血管平滑肌细胞表面膜中表达的激活的K+（BK）通道 （VSMC）和其他细胞类型。BK通道因血管内压力升高而被激活，并充当血管内压力升高的通道。 代偿机制介导血管舒张。因此，我们设想使用腺相关病毒（AAV） 递送以在动脉VSMCs中过表达BK通道，我们可以建立一个“通道储备”， 代偿性扩张蛋白，将提供长期的抗高血压治疗。基于这一前提， 该提案探讨了以下假设：通过腺病毒介导的BK通道基因的平滑肌特异性递送， 相关病毒（AAV）代表了用于长期控制高血压的疗法。令人兴奋的证据是- 原则上的研究，我们观察到，AAV介导的BK通道基因的传递可以优先地被 使用平滑肌特异性启动子靶向血管系统，这种疗法可以降低血压 在高血压小鼠中。基于这些发现，我们设计了四个具体目标，将： 通道基因传递（目的1），评估AAV传递BK通道在两个 小鼠高血压模型（目的2），评估转导的BK通道是否增强K+电流并保留 VSMC膜的正常特性（目的3），并评估AAV介导的血管扩张益处。 BK通道的体外和体内递送（目的4）。显然，为了降低高血压的发病率 在一般人群中，必须引入血管特异性、长期降压治疗 临床护理在这方面，我们项目的发现表明，使用AAV介导的递送靶向BK 动脉血管平滑肌细胞的通道在疾病的建立阶段使高血压正常化，这表明 新的抗高血压治疗范例，避免每天服用抗高血压药物。

项目成果

Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.

• DOI: 10.1371/journal.pone.0130588
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Stimers JR;Song L;Rusch NJ;Rhee SW
• 通讯作者: Rhee SW