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: 7228916
• 负责人: Louis J. Dell'Italia
• 金额: $ 34.37万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228916
• 关键词: AGTR2 gene; ANG gene; Acute; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Aortic Valve Insufficiency; Apoptosis; Attenuated; BDKRB2 gene; Biochemical; Bradykinin; Bradykinin Receptor; Caliber; Canis familiaris; Cardiac; Cardiac Myocytes; Cathepsin G; Cell surface; Chronic; Chymase; Collagen; Congestive Heart Failure; Data; Deposition; Dilatation - action; Elevation; End Point; Endopeptidases; Event; Extracellular Matrix; Extracellular Matrix Degradation; Failure; Fibroblasts; Fibrosis; Fistula; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Infiltration; Inflammation; Inflammatory; Intercellular Fluid; Kininogenase; Knockout Mice; Lead; Left Ventricular Remodeling; Matrix Metalloproteinases; Measures; Mediating; Microdialysis; Mitral Valve Insufficiency; Motion; Muscle Cells; Pathological Dilatation; Pathway interactions; Patients; Peptide Hydrolases; Production; Proteins; Rattus; Receptor, Angiotensin, Type 1; Regulation; Relative (related person); Renin-Angiotensin System; Signal Transduction; Signal Transduction Pathway; Sodium Chloride; Staging; Stimulus; Stress; Testing; Therapeutic; Thick; Time; Tissues; Transgenic Organisms; angiogenin; clinically relevant; cytokine; day; genetic inhibitor; hemodynamics; improved; in vivo; insight; mast cell; neutrophil; nitration; prevent; receptor; receptor expression; response

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.

说明(申请人提供)：血流动力学刺激在心脏间质液体(ISF)间隙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，导致细胞外基质(ECM)周转，继而导致心肌细胞定位不良、延长、肥大和细胞凋亡。在容量超负荷(VO)的心脏中，心肌细胞和ECM的持续重塑状态会导致进行性的左室扩张、胶原沉积减少(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心肌肥厚。我们严格定义了腹主动脉下腔静脉瘘(ACF)大鼠VO-HF的时间进程。这些研究描述了3个关键的临床相关时间点：急性(6小时-5天)、慢性代偿(4-8周)和慢性失代偿(15-21周)。在6-12小时内，我们发现肥大细胞的渗透和蛋白水解酶(糜酶、组织蛋白酶G)的激活与基质金属蛋白酶的激活、细胞外基质的降解和iNOS依赖的蛋白质硝化有关。VO期间ECM降解持续，ISF BK(10)和LV BK2及LV成纤维细胞AT2受体表达增加。ACF后仅用BK2受体拮抗剂治疗2天，就足以阻止ACF后5天和4周的肥大细胞浸润、iNOS依赖的蛋白硝化和ECM降解，同时减轻左室重构。这导致了一种假说，即ISF BK伴VO的急性和慢性增加是不利的LV和心肌细胞重构的基础，其早期作用于炎症，随后通过其对心脏成纤维细胞信号和功能的影响而持久。在这项提案中，AIM 1将使用体内微透析法测定ISF、BK和Ang I1，以确定BK是否参与VO进展过程中ECM的降解以及LV和心肌细胞的重构。目标2将确定在VO期间ISF BK升高的机制。目的3将确定BK在ACF进展过程中改变心脏成纤维细胞信号和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。