The Vascular Chymase-Angiotensin II System

我们已经证明，在正常心脏中，局部血管紧张素II(Ang II)的产生是分开的。 最近，我们发现非血管紧张素转换酶(ACE)途径参与了 调节血压正常的野生型小鼠的血压。相比之下，这种参与并不是 可在遗传性肥大细胞(MC)缺陷导致血管形成丧失的小鼠中表现出来 血管中的糜酶(Li，et a/.，J Clin Invest，114：112-120,2004)。此外，我们还展示了 慢性血管紧张素转换酶抑制可提高血管乳糜酶水平，支持慢性血管紧张素转换酶抑制的观点 抑制剂治疗受到非血管紧张素转换酶途径上调的限制。总而言之，这些研究已经 导致了一种争论，即局部Ang II的产生在心脏和血管中都是分开的。在……里面 支持这一点的是，发现糜酶主要存在于血管的间质空间。 血管紧张素转换酶主要分布在血管外膜和心脏间质，血管紧张素转换酶主要分布在心肌细胞的管腔表面。 血管内皮细胞。重要的是，有越来越多的证据表明，乳糜酶释放到 在病理生理应激过程中，MCs的间质间隙增加。因此，我们假设 非血管紧张素转换酶途径在肾血管性高血压的发生和发展中起关键作用 心脏和血管重塑。目标1将检验以下假设：血管非ACE途径是 通过研究MC充足和MC不足小鼠之间的差异，关键参与了血压调节 慢性肾血管性高血压。目标2将检验以下假设：非血管紧张素转换酶上调 血管紧张素转换酶抑制剂对降压和心血管有益作用的途径受限 肾血管性高血压小鼠的重塑。目标3将检验这样一种假设，即血管和 心肌脱颗粒引起的心脏病理改变主要是由于局部血管紧张素Ⅱ通过 非血管紧张素转换酶途径。建议的研究可望提供新的见解，让我们了解 血管紧张素转换酶II在血管和心脏中的形成及血管紧张素转换酶与非血管紧张素转换酶组织的相互作用 所有的发电系统。这样的见解将为管理层带来更好的治疗策略 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.