The Vascular Chymase-Angiotensin II System

我们已经表明，局部血管紧张素II（Ang II）的生产是在正常心脏区室。 最近，我们发现非血管紧张素转换酶（ACE）通路参与了 调节血压正常的野生型小鼠的血压（BP）。相比之下， 在具有遗传性肥大细胞（MC）缺陷的小鼠中可证实，所述遗传性肥大细胞（MC）缺陷导致Ang II形成的损失， 脉管系统中的糜酶（Li，等人，J Clin Invest，114：112-120，2004）。此外，我们证明， 慢性ACE抑制升高血管糜酶水平，支持慢性ACE抑制 抑制剂治疗受到非ACE途径上调的限制。综合起来，这些研究 导致了局部血管紧张素II的产生在心脏和血管中被区室化的争论。在 支持这一点的是发现糜酶主要存在于血管的间隙中， 血管紧张素转换酶（ACE）主要存在于血管外膜和心脏间质空间以及MC中;而ACE主要存在于血管外膜和心脏间质空间的管腔表面。 血管内皮细胞重要的是，有越来越多的证据表明，糜酶释放到 在病理生理应激期间，间质空间从MC增加。因此，我们假设， 非ACE途径在肾血管性高血压的发展中至关重要， 心脏和血管重塑。目的1将检验血管非ACE途径是 通过研究MC充足和缺乏小鼠之间的差异， 慢性肾血管性高血压目的2将检验非ACE基因的上调 血管紧张素转换酶抑制剂对降低血压和心血管疾病的有益作用 肾血管性高血压小鼠的重塑。目的3将检验血管和 由MC脱粒产生的心脏病理主要是由于局部Ang II的产生， 非ACE途径。这些拟议中的研究有望为我们理解 血管紧张素II如何在血管和心脏中形成，以及ACE和非ACE组织之间的相互作用 Ang II生成系统。这些见解将导致改善治疗策略的管理 心血管疾病。

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 a/., 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 patho-physiologic 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.