Osteopontin Signals between Myocytes and Fibroblasts to Regulate Cardiac Remodeling

 描述(由申请人提供)：心力衰竭是心脏疾病的常见终末期，是一个具有重大公共卫生意义的问题。尽管对病理性重塑和心力衰竭的基本机制进行了长期的研究，但目前的治疗方法仍然不足，心力衰竭的5年死亡率仍保持在50%。近年来，心脏成纤维细胞在心室重构中的作用引起了越来越多的关注，包括心脏成纤维细胞对源自应激心肌细胞的旁分泌信号的反应。了解心脏成纤维细胞和心肌细胞如何共同作用于导致心力衰竭的重塑，应该导致新的治疗策略，从而改善那些患有慢性心血管疾病的人的预后。骨桥蛋白(OPN)是一种在心肌细胞和成纤维细胞之间传递信号的分泌型蛋白。OPN通过整合素和CD44受体传递信号，在细胞的增殖、存活、黏附和迁移过程中发挥关键作用。OPN的表达在心力衰竭时被高度诱导。在一只结构性的整体基因敲除小鼠中，OPN已被证明可以促进由压力超负荷或心肌梗死(MI)引起的间质心肌纤维化。同样，通过基因缺失，CD44也被发现在MI后的体内和体外促进成纤维细胞的增殖。然而，OPN-CD44信号在心脏重构中的细胞机制仍不清楚。我们最近开发了一种新的方法来阻断OPN功能，在体内注射一种称为OPN RNA适体的蛋白质结合RNA分子。使用OPN RNA适体，我们已经证实OPN在压力超负荷诱导的左心室重构中是必需的。此外，适配子注射延缓了心力衰竭的发展。受这些结果的启发，这项应用的目标是探索OPN促进间质纤维化的细胞自主机制。通过质谱学，我们鉴定了新的OPN结合伙伴，包括细胞外基质蛋白FN1和TSP1，CD44受体，以及PI3K/Akt/mTOR途径的成员。我们的中心假设是，心脏OPN与心脏成纤维细胞和/或心肌细胞上的CD44受体结合是心室重构所必需的。我们认为，分泌型OPN与细胞外TSP1/FN1相互作用，与CD44受体结合，激活PI3K/Akt信号，导致肌成纤维细胞分化和心肌细胞肥大。

 DESCRIPTION (provided by applicant): Heart failure is the common end-stage for cardiac disease and is a problem of major public health significance. Despite longstanding research into the basic mechanisms underlying pathological remodeling and heart failure, current therapies remain inadequate, and 5-year mortality for heart failure remains at 50%. Recently, there has been increasing interest in the role of cardiac fibroblasts in ventricular remodeling, including ho cardiac fibroblasts respond to paracrine signals originating in the stressed myocyte. Understanding how cardiac fibroblasts and myocytes together contribute to remodeling resulting in heart failure should lead to new therapeutic strategies that will improve the prognosis for those with chronic cardiovascular conditions. Osteopontin (OPN) is a secreted protein that signals between cardiac myocytes and fibroblasts. OPN plays pivotal roles in the regulation of proliferation, survival, adhesion, and migration of cells by signaling through integrin and CD44 receptors. OPN expression is highly induced in heart failure. Using a constitutive, global knockout mouse, OPN has been shown to promote the interstitial myocardial fibrosis induced by pressure overload8 or myocardial infarction (MI). Similarly, by gene deletion, CD44 has been found to promote fibroblast proliferation in vivo after MI and in vitro. However, the cellular mechanisms conferring OPN-CD44 signaling in cardiac remodeling remain unknown. We have recently developed a novel method by which to block OPN function, in vivo injection of a protein-binding RNA molecule called OPN RNA aptamer. Using the OPN RNA aptamer, we have confirmed that OPN is required for pressure overload-induced left ventricular remodeling. Moreover, aptamer injection attenuated the development of heart failure. Inspired by these results, the goal of this application is to explore the cell autonomous mechanisms by which OPN contributes to interstitial fibrosis. By mass spectroscopy, we have identified novel OPN binding partners, including extracellular matrix proteins Fibronectin-1 (FN1) and Thrombopondin-1 (TSP1), CD44 receptors, and members of the PI3K/Akt/mTOR pathway. Our central hypothesis is that the binding of cardiac OPN to CD44 receptors on cardiac fibroblasts and/or myocytes is essential for ventricular remodeling. We propose that secreted OPN interacts with extracellular TSP1/FN1, binds to CD44 receptors, and activates PI3K/Akt signaling resulting in myofibroblast differentiation and myocyte hypertrophy.