The Vascular Chymase-Angiotensin II System

描述（由申请人提供）：我们已经证明，在正常心脏中，局部血管紧张素II （Ang II）的产生是区隔的。最近，我们发现非血管紧张素转换酶（ACE）途径参与调节正常血压野生型小鼠的血压（BP）。相比之下，在遗传肥大细胞（MC）缺陷的小鼠中，这种参与没有被证明（Li, et al., J clinin Invest, 114:112- 120,2004）。此外，我们证明慢性ACE抑制可提高血管溶酶水平，支持慢性ACE抑制剂治疗受非ACE途径上调限制的观点。综上所述，这些研究导致了局部Ang II的产生在心脏和血管中都是区隔的争论。支持这一观点的发现是，乳糜酶主要存在于血管外膜的间质空间和心脏间质空间以及MCs中；而ACE主要存在于血管内皮细胞的管腔表面。重要的是，越来越多的证据表明，在病理生理应激期间，MCs向间质释放的乳糜酶增加。因此，我们假设非ace途径在肾血管性高血压的发展和由此产生的不良心脏和血管重构中起关键作用。目的1将通过研究mc -充足小鼠和mc -缺乏小鼠慢性肾血管性高血压之间的差异，验证血管非ace通路在血压调节中起关键作用的假设。Aim 2将验证非ace途径的上调限制ACEi治疗对肾血管性高血压小鼠血压降低和心血管重塑的有益作用的假设。目的3将检验MC脱颗粒产生的血管和心脏病理主要是由于通过非ace途径产生局部Ang II的假设。拟议的研究有望为我们理解血管和心脏中Ang II的形成以及ACE和非ACE组织中Ang II生成系统之间的相互作用提供新的见解。这些见解将导致改善心血管疾病管理的治疗策略。

DESCRIPTION (provided by applicant): We have shown that local angiotensin II (Ang II) production is compartmentalized in the normal heart. Recently, we showed the involvement of the non-angiotensin-converting enzyme (ACE) pathway in regulating blood pressure (BP) in normotensive wild type mice. In contrast, this involvement is not demonstrable in mice with a genetic mast cell (MC) deficiency that causes a loss of Ang ll-forming chymases in the vasculature (Li, et al., J Clin Invest, 114:112-120, 2004). Moreover, we demonstrated that chronic ACE inhibition elevates vascular chymase levels, supporting the contention that chronic ACE inhibitor therapy is limited by up-regulation of the non-ACE pathway. Taken together, these studies have led to the contention that local Ang II production is compartmentalized in both heart and blood vessels. In support of this is the finding that chymase is predominantly in the interstitial space of the vascular adventitia and cardiac interstitial space and in MCs; while ACE is mainly found on the luminal surface of vascular endothelial cells. Importantly, there is increasing evidence that chymase release into the interstitial space is increased from MCs during pathophysiologic stress. Accordingly, we hypothesize that the non-ACE pathway is critical in the development of renovascular hypertension and resultant adverse cardiac and vascular remodeling. Aim 1 will test the hypothesis that the vascular non-ACE pathway is critically involved in BP regulation by studying differences between MC-sufficient and -deficient mice with chronic renovascular hypertension. Aim 2 will test the hypothesis that the up-regulation of the non-ACE pathway limits the beneficial effects of ACEi therapy on blood pressure reduction and cardiovascular remodeling in mice with renovascular hypertension. Aim 3 will test the hypothesis that the vascular and cardiac pathology produced by MC degranulation is principally due to local Ang II production via the non-ACE pathway. The proposed studies are expected to provide new insights into our understanding of how Ang II is formed in blood vessels and the heart and the interplay between ACE and non-ACE tissue Ang ll-generating systems. Such insights will lead to improved therapeutic strategies for the management of cardiovascular diseases.