Myofibroblasts and fibrosis after cardiac transplant

心脏移植后的肌成纤维细胞和纤维化

• 批准号: 6659328
• 负责人: ARTHUR ROGER STRAUCH
• 金额: $ 30.51万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659328
• 关键词: cardiac myocytes; fibroblasts; fibrosis; free radical oxygen; heart cell; heart transplantation; human tissue; laboratory mouse; oxidative stress; stress proteins; transforming growth factors; transplant rejection; vascular smooth muscle; wound healing

Chronic rejection in the transplanted heart is associated with interstitial fibrosis and progressive neointimal lesion formation in the coronary arterial bed that impairs tissue perfusion to the point of functional disruption. Our intention in Project 3 is to examine wound repair processes in the transplanted heart that specifically involve activated stromal myofibroblasts. We propose that alloantigen-independent ischemia/reperfusion injury during the early post-operative period as well as chronic, alloantigen-dependent release of TGFbeta1 in long-term accepted grafts promote myofibroblasts activation and histogenic remodeling via a common signaling pathways based on reactive oxygen species (ROS). Myofibroblasts accumulate in the coronary adventitia and cardiac interstitium of heart grafts where they express several injury- response genes that are regulated by MSYI, a cold-shock domain (CSD) transcriptional regulatory protein. MSY1 and related proteins are important mediators of the transcriptional response to tissue stress and redox imbalance. The goal of the proposed research is to examine TGFbeta1- and ROS-dependent changes in MSY1 protein complexes that govern VSM alpha-actin promoter activity. Mis-regulation of VSM alpha-actin expression during chronic rejection is associated with accumulation of myofibroblasts, fibrocontractile scar tissue, neointimal smooth muscle cells, and poorly differentiated cardiomyocytes. VSM alpha-actin is encoded by a prototypical injury response gene that shares MSY1 control elements with other genes required for wound repair. Analysis of interactions between MSY1 and other TRPs required for injury-response gene expression in human stromal myofibroblasts should provide new information about molecular control points in chronic rejection. In human pathology and intramyocardial biopsy samples, assessment of MSY1:TRP structure and function may provide new prognostic indicators for evaluating and staging chronic rejection in transplant patients before the development of graft-destructive fibrosis. From the standpoint of transplant vascular sclerosis, studiers of stromal myofibroblasts are especially relevant given the demonstrated importance of adventitial fibroblasts in neointima formation as well as the establishment of new microvascular perfusion circuits that are critical for long-term heart graft survival. Finally, TGFbeta1 and/or ROS may modulate expression of other MSY1-dependent, chronic rejection- associated genes such as those encoding MHC class II molecules which compliments Project 1 and 2 aims pertaining to alloantibody production, monocyte/macrophage FcR engagement, and the role of TGFbeta1 in graft acceptance vs. fibrosis.

移植心脏的慢性排斥反应与间质纤维化和冠状动脉床上进行性新的内膜病变形成有关，这些病变损害了组织的灌注量，直至功能中断。我们在项目3中的意图是检查移植心脏中的伤口修复过程，特别是涉及激活的间质肌成纤维细胞。我们认为，术后早期同种异体非抗原依赖的缺血/再灌注损伤以及长期接受的移植物中慢性、同种异体抗原依赖的TGFbeta1的释放通过基于活性氧(ROS)的共同信号通路促进肌成纤维细胞的激活和组织发生重构。心肌成纤维细胞聚集在心脏移植物的冠脉外膜和心脏间质中，在那里它们表达几个受冷休克结构域(CSD)转录调控蛋白MSYI调控的损伤反应基因。MSY1及其相关蛋白是组织应激反应和氧化还原失衡的重要转录调节因子。这项拟议研究的目的是检测控制VSMα-肌动蛋白启动子活性的MSY1蛋白复合体中依赖于TGFbeta1和ROS的变化。慢性排斥反应中VSMα-肌动蛋白表达的错误调节与肌成纤维细胞、纤维收缩瘢痕组织、新生内膜平滑肌细胞和低分化心肌细胞的聚集有关。VSMα-肌动蛋白由一个典型的损伤反应基因编码，该基因与伤口修复所需的其他基因共享MSY1控制元件。分析MSY1与人类间质肌成纤维细胞损伤反应基因表达所需的其他TRPs之间的相互作用，将为慢性排斥反应中的分子控制点提供新的信息。在人类病理学和心肌内活检标本中，MSY1：Trp结构和功能的评估可能为移植患者在发生移植物破坏性纤维化之前评估和分期慢性排斥反应提供新的预后指标。从移植血管硬化的角度来看，间质肌成纤维细胞的研究尤其重要，因为外膜成纤维细胞在新生内膜形成中的重要性以及对心脏移植物长期存活至关重要的新的微血管灌流回路的建立。最后，TGFbeta1和/或ROS可能调节其他MSY1依赖的慢性排斥相关基因的表达，例如那些编码MHC II类分子的基因，它补充了项目1和2的目标，涉及同种异体抗体的产生，单核/巨噬细胞FCR的结合，以及TGFbeta1在移植物接受与纤维化中的作用。