Angiotensin II and Bradykinin in Cardiac Hypertrophy

血管紧张素 II 和缓激肽在心脏肥大中的作用

• 批准号: 6776319
• 负责人: Louis J. Dell'Italia
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776319
• 关键词: ACE inhibitors; angiotensin II; angiotensin receptor; bradykinin; cardiac myocytes; chymase; collagen; congestive heart failure; cytoprotection; disease /disorder model; extracellular matrix; fibroblasts; genetically modified animals; heart enlargement; heart valve disorder; hemodynamics; interstitial; kallikreins; laboratory mouse; laboratory rat; pathologic process; pharmacokinetics; renin; renin angiotensin system

DESCRIPTION (provided by applicant): Hemodynamic stimuli set in motion a sequence of biochemical and inflammatory events in the cardiac interstitial fluid (ISF) space that interact with cell surface molecules to dictate extracellular matrix (ECM) turnover with subsequent maladaptive myocyte orientation, elongation, hypertrophy and apoptosis. In hearts with volume overload (VO), a continual state of remodeling of myocyte and ECM results in a progressive LV dilatation, decreased collagen deposition (in spite of increased cardiac angiotensin II (ANG II) expression), increased LV wall stress, and congestive heart failure (HF). However, we and others have shown that blockade of the renin-angiotensin system does not improve VO cardiac hypertrophy. We have rigorously defined the temporal progression of VO HF in the rat subjected to aortocaval fistula (ACF). These studies have characterized 3 key, clinically relevant, time points: acute (6 hrs-5 days), chronic compensated (4-8 wks) and chronic decompensated (15-21 wks). We found mast cell infiltration and protease activation (chymase, cathepsin G) associated with MMP activation, ECM degradation, and iNOS-dependent protein nitration within 6-12 hrs. ECM degradation persisted and ISF BK (10) and LV BK2 and LV fibroblast AT2 receptor expression were increased during VO. Treatment with BK2 receptor antagonist for only 2 days after ACF was sufficient to prevent mast cell infiltration, iNOS-dependent protein nitration, and ECM degradation at 5 days and 4 wks of ACF, while attenuating LV remodeling. This led to the hypothesis that acute and chronic increases in ISF BK with VO underlies the adverse LV and cardiomyocyte remodeling initiated by its early effect on inflammation and subsequently perpetuated by its effect on cardiac fibroblast signaling and function. In this proposal, AIM 1 will determine whether BK mediates ECM degradation and LV and cardiomyocyte remodeling during the progression of VO using in-vivo microdialysis to measure ISF BK and ANG I1. AIM 2 will determine the mechanisms by which ISF BK is elevated during VO. Aim 3 will determine the mechanisms by which BK alters cardiac fibroblast signaling and expression of ECM modulatory proteins during the progression ACF. These studies will uncover new mechanistic insights and therapeutic strategies for VO.

描述（由申请人提供）：血流动力学刺激在心脏间质液（ISF）空间中启动一系列生化和炎症事件，这些事件与细胞表面分子相互作用，决定细胞外基质（ECM）周转以及随后的适应不良的肌细胞定向、伸长、肥大和凋亡。 在容量超负荷 (VO) 的心脏中，肌细胞和 ECM 的持续重塑状态导致进行性左室扩张、胶原蛋白沉积减少（尽管心脏血管紧张素 II (ANG II) 表达增加）、左室壁应力增加和充血性心力衰竭 (HF)。 然而，我们和其他人已经证明，阻断肾素-血管紧张素系统并不能改善 VO 心脏肥大。 我们严格定义了患有主动脉腔静脉瘘 (ACF) 的大鼠 VO HF 的时间进展。 这些研究描述了 3 个关键的临床相关时间点：急性（6 小时至 5 天）、慢性代偿期（4-8 周）和慢性失代偿期（15-21 周）。 我们发现肥大细胞浸润和蛋白酶激活（糜酶、组织蛋白酶 G）与 MMP 激活、ECM 降解和 6-12 小时内 iNOS 依赖性蛋白质硝化相关。 ECM 降解持续存在，ISF BK (10) 和 LV BK2 以及 LV 成纤维细胞 AT2 受体表达在 VO 期间增加。 ACF 后仅 2 天用 BK2 受体拮抗剂治疗就足以防止肥大细胞浸润、iNOS 依赖性蛋白质硝化和 ACF 5 天和 4 周时的 ECM 降解，同时减弱左室重塑。 这导致了这样的假设：ISF BK 随 VO 的急性和慢性增加是不良左心室和心肌细胞重塑的基础，这种重塑是由其对炎症的早期影响引发的，随后通过其对心脏成纤维细胞信号传导和功能的影响而持续存在。 在该提案中，AIM 1 将使用体内微透析测量 ISF BK 和 ANG I1 来确定 BK 是否介导 VO 进展过程中的 ECM 降解以及 LV 和心肌细胞重塑。 AIM 2 将确定 VO 期间 ISF BK 升高的机制。 目标 3 将确定 BK 在 ACF 进展过程中改变心脏成纤维细胞信号传导和 ECM 调节蛋白表达的机制。 这些研究将揭示 VO 的新机制见解和治疗策略。