CARDIAC MAST CELL--ROLE IN PATHOGENESIS OF HEART FAILURE

心脏肥大细胞——在心力衰竭发病机制中的作用

• 批准号: 6383280
• 负责人: Joseph S Janicki
• 金额: $ 2.86万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6383280
• 关键词: atrial natriuretic peptide; cardiac myocytes; collagen; collagenase; cytokine; enzyme activity; extracellular matrix; fibroblasts; heart failure; heart metabolism; heart pharmacology; histogenesis; intracardiac volume; laboratory rat; mast cell; myocardium; pathologic process; tissue /cell culture; ventricular hypertrophy

Chronic ventricular volume overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. However, the compensatory hypertrophy and ventricular dilatation induced by this condition ultimately has a detrimental affect on ventricular function, resulting in heart failure. A suitable explanation for this pathologic remodeling has not been established, although myocardial collagen fiber degradation represents a common pathway that could produce these adverse structural and architectural alterations. Fibrillar collagen provides the framework which interconnects the cardiomyocytes and blood vessels in the myocardium, thereby maintaining ventricular shape and size and contributing to tissue stiffness. These myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. Activation of myocardial metalloproteinases (i.e., collagenase) has been implicated in this adverse ventricular remodeling, however, virtually no studies have been performed to elucidate how this activation occurs in the heart. Recent evidence from our laboratory indicates that mast cell degranulation is responsible for collagenase activation in chronic volume overload. The proposed studies are designed to test the hypothesis that cardiac mast cells contribute to the pathologic ventricular remodeling which precedes the development of heart failure. Accordingly, this proposal will use infrarenal aortocaval fistula and myocardial infarction models of chronic volume overload in rats to examine the role of cardiac mast cells at the organ, tissue, and cellular levels. The specific aims of the proposal are 1) to determine: if cardiac mast cells are involved in the myocardial remodeling process; whether mast cell phenotype and/or protein expression change during this process; and mast cell sensitivity to cytokines, ANP, and other neuroendocrine hormones; 2) to assess the ability of mast cell secretory products to regulate cardiac mast cell density and the synthesis and degradation of the cardiac ECM as well as their effect on the interaction of cardiac myocytes and fibroblasts with the ECM; and 3) to determine whether pharmacological inhibition of the mast cell- induced MMP activation cascade will prevent the development of heart failure. These studies will utilize a variety of physiologic, morphologic, biochemical, and molecular techniques to characterize the role of cardiac mast cells in the ventricular remodeling at critical pathological stages in the development of heart failure.

慢性心室容量超负荷导致心肌的肌肉、血管和细胞外基质成分的结构重塑。 然而，这种情况引起的代偿性肥大和心室扩张最终对心室功能产生不利影响，导致心力衰竭。 尽管心肌胶原纤维降解代表了可能产生这些不良结构和建筑改变的常见途径，但尚未建立这种病理性重塑的适当解释。 纤维胶原蛋白提供了将心肌细胞和心肌中的血管互连的框架，从而维持心室形状和大小并有助于组织硬度。 这些心肌胶原纤维必须被破坏，心室扩张，球化和壁变薄发生。 心肌金属蛋白酶的激活（即，胶原酶）与这种不利的心室重塑有关，然而，实际上没有进行研究来阐明这种激活如何在心脏中发生。 我们实验室的最新证据表明，肥大细胞脱颗粒是慢性容量超负荷时胶原酶激活的原因。 本研究旨在验证心肌肥大细胞参与心力衰竭发生前病理性心室重构的假设。 因此，本提案将使用肾下腔静脉瘘和慢性容量超负荷的大鼠心肌梗死模型，以检查心脏肥大细胞在器官，组织和细胞水平上的作用。 该提案的具体目的是1）确定：心脏肥大细胞是否参与心肌重塑过程;肥大细胞表型和/或蛋白质表达在该过程中是否发生变化;以及肥大细胞对细胞因子、ANP和其他神经内分泌激素的敏感性;（二）评估肥大细胞分泌产物调节心脏肥大细胞密度以及心脏ECM合成和降解的能力作为它们对心肌细胞和成纤维细胞与ECM相互作用的影响;和3）确定肥大细胞诱导的MMP活化级联的药理学抑制是否将防止心力衰竭的发展。 这些研究将利用各种生理学、形态学、生物化学和分子技术来表征心脏肥大细胞在心力衰竭发展的关键病理阶段的心室重构中的作用。