Evaluation of MicroRNA Mechanisms Involved in Collagen Matrix Therapy for Myocardial Infarction

Abstract

Myocardial infarction (MI), a late-stage event of many cardiovascular diseases (CVD), results in cardiomyocyte death, myeloid cell recruitment to promote cellular debris removal and excessive cardiac remodeling affecting architecture and function, which can ultimately lead to heart failure. Currently, the use of biomaterials to intervene on the hostile post-MI environment and promote myocardial healing is being investigated to restore cardiac function. It has been shown that an injectable collagen matrix improves cardiac repair by altering macrophage polarization, reducing cell death and enhancing angiogenesis, leading to a reduction in infarct size and improved cardiac function when delivered at 3 hours post-MI. MicroRNAs (miRNA) “fine tune” gene expression by negatively regulating the translational output of target messenger RNA (mRNA). As such, miRNAs present interesting therapeutic opportunities for the treatment of MI. However, the delivery of miRNA mimics and/or inhibitors can be complicated by degradation and off target effects. The objectives of this thesis were to determine how the matrix may regulate endogenous miRNAs and to explore the biomaterial’s ability to deliver therapeutic miRNAs. It was shown that matrix treatment of MI mouse hearts resulted in altered expression of 119 miRNAs, some of which had functions linked to the beneficial effects of matrix treatment. Of particular interest, miR-92a was down-regulated within the infarct and peri-infarct cardiac tissue 2 days after matrix treatment (delivered at 3-hours post-MI) compared to PBS treatment. In in vitro cultures, the matrix down-regulated miR-92a levels in macrophages but did not significantly alter miR-92a expression in endothelial cells, circulating angiogenic cells or fibroblasts. In addition, using an in vitro model system, it was shown that the matrix may have the potential to deliver functional therapeutic miRNAs to cells; however further experimental optimisation is required to confirm these results. Therefore, collagen matrix treatment may be a promising approach to regulate and/or deliver miRNAs for protecting the myocardial environment and improving function of the infarcted heart.