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

项目摘要 原发性高血压是一种多基因疾病，全球有近10亿人患病。它预先设置了 到心肌肥厚、中风和慢性肾功能衰竭。在提供降压药的个体中，只有 三分之一的人实现血压控制，原因是成本高、副作用大以及与 经常需要的日常的多种药物治疗。在这方面，血管扩张剂的长期表达 蛋白质将是非常有利的，以避免与日常生活相关的高成本和不便 给药，也是为了将短效引起的血压波动降到最低 抗高血压药物。作为一种候选血管扩张蛋白，人们主要感兴趣的是高电导，钙- 表达于血管平滑肌细胞表膜上的激活K+(BK)通道 (VSMCs)和其他细胞类型。BK通道在血管内压升高时被激活，并起到 调节血管扩张的代偿机制。因此，我们设想使用腺相关病毒(AAV) 在动脉VSMC中过度表达BK通道，可以建立起一种通道储备 代偿性扩张器蛋白，将提供长期的抗高血压治疗。基于这个前提，这个 Proposal探索了这样的假设：通过腺体-BK通道基因的平滑肌专一性递送- 相关病毒(AAV)代表了一种长期控制高血压的治疗方法。令人振奋的证据是- 在原理研究中，我们观察到AAV介导的BK通道基因的传递可以优先 以血管系统为靶点，使用平滑肌特异性启动子，这种疗法可以降低血压 在高血压小鼠身上。基于这些发现，我们设计了四个具体目标：优化BK 通道基因传递(目标1)，评估AAV传递BK通道的降压效果 高血压小鼠模型(目标2)，评估转导的BK通道是否增强K+电流并保持 VSMC膜的正常特性(目标3)，并评价AAV介导的血管扩张剂的益处 体外和体内BK通道的传递(目标4)。显然，为了减少高血压的发病率 在普通人群中，必须引入针对血管的长期降压治疗。 临床护理。在这方面，我们项目的发现表明，使用AAV介导的递送来靶向BK 动脉VSMCs的通道在疾病的建立阶段使高血压正常化，提示 避免每日服用降压药的降压治疗新范例。

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.