The Vascular Chymase-Angiotensin II System

描述(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)的产生是分开的。最近，我们发现非血管紧张素转换酶(ACE)途径参与了正常血压野生型小鼠的血压调节。相反，这种参与在遗传肥大细胞(MC)缺乏的小鼠中并不明显，这种缺乏导致血管系统中血管形成糜酶的丧失(Li等人，J Clin Invest，114：112-120,2004)。此外，我们还证明了慢性ACE抑制可提高血管乳糜酶水平，支持慢性ACE抑制剂治疗受限于非ACE途径上调的观点。综上所述，这些研究导致了这样一种观点，即局部Ang II的产生在心脏和血管中都是分开的。支持这一观点的是，Chymase主要分布在血管外膜和心脏间质的间质以及MC中，而ACE主要分布在血管内皮细胞的管腔表面。重要的是，越来越多的证据表明，在病理生理应激过程中，巨噬细胞向间质释放的糜酶增加。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展和由此产生的不利的心脏和血管重塑中起关键作用。目的1通过研究MC充足和MC缺乏的慢性肾血管性高血压小鼠之间的差异，验证血管非ACE途径在血压调节中的重要作用。目的2验证非血管紧张素转换酶途径的上调限制了血管紧张素转换酶抑制剂对肾性高血压小鼠降压和心血管重塑的有利作用的假说。目的3将验证这样一种假设，即MC脱颗粒引起的血管和心脏病理主要是由于局部Ang II通过非ACE途径产生的。这些拟议的研究有望为我们理解血管和心脏如何形成血管紧张素转换酶II以及血管紧张素转换酶和非血管紧张素转换酶组织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.