Angiotensin II and Bradykinin in Cardiac Hypertrophy

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）更新，随后出现适应不良的肌细胞定向、伸长、肥大和凋亡。 在容量超负荷（VO）心脏中，肌细胞和ECM的持续重塑状态导致进行性LV扩张、胶原沉积减少（尽管心脏血管紧张素II（ANG II）表达增加）、LV壁应力增加和充血性心力衰竭（HF）。 然而，我们和其他人已经表明，阻断肾素-血管紧张素系统并不能改善VO心肌肥大。 我们已经严格定义的时间进展VO HF大鼠下腔静脉瘘（ACF）。 这些研究表征了3个关键的临床相关时间点：急性（6小时-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iNOS依赖性蛋白硝化6-12小时内。 在VO期间，ECM降解持续存在，ISF BK（10）和LV BK 2和LV成纤维细胞AT 2受体表达增加。 ACF后仅用BK 2受体拮抗剂治疗2天就足以防止ACF后5天和4周的肥大细胞浸润、iNOS依赖性蛋白硝化和ECM降解，同时减弱LV重塑。 这导致了这样的假设，即伴有VO的ISF BK的急性和慢性增加是不利的LV和心肌细胞重塑的基础，该重塑由其对炎症的早期作用引发，随后通过其对心脏成纤维细胞信号传导和功能的作用而延续。 在该提案中，AIM 1将使用体内微透析来测量ISF BK和ANG I1，以确定BK是否介导VO进展期间的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。 目的3探讨BK在ACF进展过程中改变心肌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的新机制和治疗策略。

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.