MicroRNA-15b/FGF-2通路介导FMT调控心梗后心肌纤维化进程及机制研究

Myocardial fibrosis is a characteristic pathologic feature in cardiac remodeling process and also a critical component of ventricular dysfunction and reduced compliance after myocardial infarction. Studies demonstrated that the uncontrolled promotion of cardiac fibroblast to myofibroblast transition (FMT) greatly contributes to the massive myocardial fibrosis and malignant ventricular remodeling after myocardial infarction. Our previous studies have found that miR15b suppressed the revascularization progress after femoral artery ligation through regulating AKT3/eNOS pathway. While during the observation of the relationship between miR15b and myocardial infarction, we have found that inhibition of miR15b expression increased the degree of myocardial fibrosis in mice after myocardial infarction, and meanwhile miR15b probably participated in the FMT course of cardiac fibroblasts via affecting its downstream target gene FGF2. So, in this study we plan to systemically reveal the action of miR15b/FGF2 pathway in the FMT course and its mechanism, and attempt to realize the effective control of the excessive FMT from the aspect of epigenetic regulation, for providing a new treating target to develop the new anti-myocardial fibrotic drugs.

心肌纤维化是心肌梗死后心脏重构的特征性病理改变，亦是导致心梗后心室功能恶化及顺应性降低的主要因素。研究表明，成纤维细胞向肌成纤维细胞转变（FMT）过程的失控是心梗后心肌广泛纤维化、心室恶性重塑形成的重要原因。我们课题组前期的研究揭示miR15b通过调控AKT3/eNOS抑制股动脉结扎后再血管化进程，而在探索miR15b与心肌梗死关系中发现，抑制miR15b的表达会加重心梗小鼠心肌纤维化程度，同时miR15b或许是通过影响下游FGF2靶基因的功能，参与到心肌成纤维细胞FMT过程当中。因此，本研究拟通过动物、细胞实验及临床分析，全面探明miR15b/FGF2通路对于心梗后FMT过程的影响及机制，力图从microRNA角度实现对心梗后过度FMT过程的有效抑制，为开发新型抗心肌纤维化药物提供新的靶点。

心肌梗死后心肌纤维化是导致心梗后心力衰竭的重要原因。造成心肌梗死后心室重构的机制复杂，是多因素相互作用，共同参与的结果。近期研究显示，微小RNA在肺、肾脏等诸多器官的纤维化过程中起重要的调控作用。然而微小RNA在心肌梗死，特别是心肌梗死后心肌纤维化中的作用及机制尚不明确。本项目以MicroRNA-15b为切入点，探讨了其调控心肌成纤维细胞表型转变，进而影响心肌梗死后心肌纤维化的作用机制。本项目研究结果表明，MicroRNA-15b通过调节 FGF2/MAPK 信号通路介导心肌梗死后心肌纤维化过程。我们证明，MicroRNA-15b的表达在心肌梗死后以时间依赖性方式增加。此外，抑制MicroRNA-15b会促进成纤维细胞-肌成纤维细胞转变 (FMT)，进而加速心肌纤维化和细胞外基质 (ECM) 重塑的过程。在大鼠心脏成纤维细胞 (RCF) 中，抑制MicroRNA-15b的表达同样加速了细胞的增殖、迁移以及FMT 过程，而MicroRNA-15b的过表达在RCF中导致相反的结果。在RCF中通过 siRNA 敲低FGF2部分挽救了MicroRNA-15b缺失所导致的细胞表型改变。该项目的研究结果为阐明心肌梗死后心肌纤维化的发病机制提供了新的理论依据，同时为心肌纤维化的防治和新药研发提供了潜在靶点和新思路。