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）的产生是区室化的。最近，我们发现非血管紧张素转换酶（ACE）途径参与调节血压正常野生型小鼠的血压（BP）。相比之下，这种参与在具有遗传性肥大细胞（MC）缺陷的小鼠中是不明显的，所述遗传性肥大细胞缺陷导致血管系统中Ang II形成糜酶的损失（Li，et al. J Clin Invest，114：112-120，2004）。此外，我们证明了慢性ACE抑制剂升高血管糜酶水平，支持慢性ACE抑制剂治疗受非ACE途径上调限制的论点。总的来说，这些研究导致了局部Ang II产生在心脏和血管中被区室化的论点。支持这一点的发现是，糜酶主要存在于血管外膜和心脏间质空间的间质空间和MC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，从MC释放到间质空间的糜酶增加。因此，我们假设非ACE通路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塑中至关重要。目的1将通过研究MC充足和缺乏的慢性肾血管性高血压小鼠之间的差异来验证血管非ACE通路在BP调节中起关键作用的假设。目的2将检验非ACE通路的上调限制ACEi治疗对肾血管性高血压小鼠的血压降低和心血管重构的有益作用的假设。目的3将检验由MC脱粒产生的血管和心脏病理主要是由于通过非ACE途径的局部Ang II产生的假设。预期所提出的研究将为我们理解血管紧张素II如何在血管和心脏中形成以及ACE和非ACE组织血管紧张素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治疗策略的心血管疾病的管理。

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.