Carmen Fitzpatrick

Introduction. Cardiac fibrosis primarily occurs after an acute myocardial infarction due to an aberrant innate inflammatory and repair response. Often, the fibrotic repair response contributes to early onset heart failure which leads to a rapidly declining quality of life. Current therapeutic methods lack appropriate prevention of the overzealous fibrotic repair process; there is growing interest in more tailored biological therapies, such as miRNA. Various studies show miRNA-21 is a crucial mediator since it aids the progression of excessive fibrosis in the heart. Therefore, development of a synthetic miR-21 inhibitor holds promise in preventing fibrosis-related heart failure. Methods. In the small animal model (mice) study, pressure overload is induced by a transverse aortic constriction (TAC) procedure to form a controlled infarct area in the heart. The experimental group consisted of a macrophage-specific miR-21 knock out; findings were compared to a control group. In the larger animal model (pig) study, investigators induced a controlled infarct by occluding the LAD artery for 60 minutes. The experimental groups of this larger animal model included a sham (only injury was the incision), heart failure control group (infarct induced without application of inhibitor), infarct induced with standard miRNA inhibitor administered, and infarct induced with specific miR-21 inhibitor administered. Results. The cardiac macrophages recruited to the infarct site were found to have an upregulation in miR-21 activity. miR-21 upregulation results in fibroblast proliferation. miR-21 was also found to polarize macrophages toward an M1 phenotype rather than an M2 phenotype. The excess in M1 (pro-inflammatory) macrophages increases the cross-sectional area of infarct and subsequently increases the size of the fibrosis. An effective reduction in the amount of fibrosis using synthetic LNA-miR-21 inhibitor showed a reduction in the number of fibroblasts and cardiac macrophages. Conclusions. Several investigators provided various probable signaling mechanisms by which miR-21 may upregulate fibrosis. However, all studies agreed that miR-21 inhibition is a promising means to preventing excess fibrotic tissue development in the heart after an AMI. The proposed delivery in humans would entail delivering the miR-21 inhibitor via established cardiac catheterization methods; delivery of the inhibitor needs to be as close to the area of infarct as possible to minimize off-target effects.

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