The Vascular Chymase-Angiotensin II System

血管糜酶-血管紧张素 II 系统

• 批准号: 7570032
• 负责人: AHSAN HUSAIN
• 金额: $ 37.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570032
• 关键词: AGTR2 gene; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Arterial Fatty Streak; Atherosclerosis; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Degranulation; Chronic; Chymase; Development; Doctor of Philosophy; Endothelial Cells; Enzyme Inhibition; Enzymes; Functional disorder; Generations; Genetic; Heart; Heart Hypertrophy; Immunohistochemistry; Infiltration; Ischemia; Laboratories; Lead; Maintenance; Measures; Microdialysis; Molecular; Mus; Organ; Pathology; Patients; Peptidyl-Dipeptidase A; Physiological; Plasma; Principal Investigator; Production; Property; Relative (related person); Renovascular Hypertension; Resistance; Role; Rupture; Stress; Surface; System; Testing; Therapeutic; Tissues; Treatment Efficacy; Tunica Adventitia; Up-Regulation; Vascular Endothelial Cell; Vascular remodeling; Wild Type Mouse; attenuation; base; blood pressure regulation; enzyme deficiency; enzyme pathway; human tissue; improved; in vivo; insight; interstitial; kidney vascular structure; mast cell; non-genetic; normotensive; pressure; receptor; response

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.

描述（由申请人提供）：我们已经表明，局部血管紧张素II（ANG II）的产生在正常心脏中被划分。最近，我们展示了非血管紧张素转换酶（ACE）途径在调节正常野生型小鼠中调节血压（BP）中的参与。相比之下，这种参与在具有遗传肥大细胞（MC）缺乏的小鼠中不能证明，这会导致脉管系统中ANG LL形成的辣椒酶损失（Li等，J Clin Invest，114：112-120，2004）。此外，我们证明了慢性ACE抑制会提高血管卫生酶水平，这支持了这样一种观点，即慢性ACE抑制剂治疗受到非ACE途径的上调限制。综上所述，这些研究导致了一个观点，即心脏和血管中局部ANG II的产生均被分类。为此，发现Chymase主要是在血管外膜和心脏间质空间以及MC中的间质空间中。 ACE主要在血管内皮细胞的腔表面上发现。重要的是，有越来越多的证据表明，在病理生理应力期间，MCS增加了Chymase释放到间质空间中。因此，我们假设非ACE途径对于肾血管高血压以及导致的不良心脏和血管重塑至关重要。 AIM 1将检验以下假设，即通过研究慢性肾血管高血压的MC富度和缺陷小鼠之间的差异，血管非ACE途径与BP调节有关。 AIM 2将检验以下假设：非ACE途径的上调限制了ACEI治疗对肾血管高血压小鼠血压降压和心血管重塑的有益作用。 AIM 3将检验以下假设：MC脱粒产生的血管和心脏病理主要是由于非ACE途径的局部ANG II产生。预计拟议的研究将为我们对ANG II在血管以及心脏和非ACE组织ANG ANG-LL生成系统之间的相互作用中的理解提供新的见解。这种见解将导致改善心血管疾病管理的治疗策略。