Cell type-specific microRNA therapies for myocardial infarction

Abstract

Current interventions fail to recover injured myocardium after infarction and prompt the need for development of cardioprotective strategies. Of increasing interest is the therapeutic use of microRNAs to control gene expression through specific targeting of mRNAs. In this Review, we discuss current microRNA-based therapeutic strategies, describing the outcomes and limitations of key microRNAs with a focus on target cell types and molecular pathways. Last, we offer a perspective on the outlook of microRNA therapies for myocardial infarction, highlighting the outstanding challenges and emerging strategies.

Fig. 1.. Summary of myocardial infarct progression with a focus on the role of each cell type.

Immediately after infarction, the inflammatory phase begins and is characterized by irreversible cell death of all cell types in the infarct and the initiation of the inflammatory process through cytokine release. Next, the proliferative phase is characterized by the activation of CFs and the initiation of scar development. Macrophages also undergo polarization and switch to an anti-inflammatory phenotype during this phase. The maturation phase is characterized by cardiomyocyte hypertrophy in response to increased cardiac demand and the maturation of the scar that forms over the infarcted area. Last, long-term remodeling is characterized by pathological changes including maladaptive cardiomyocyte hypertrophy, chronic overactivation of CFs, decreased vascular density, and reemergence of an inflammatory response.

Fig. 2.. Summary of miRNAs surveyed in this Review.

For each study, in this Review, we categorized the overall effect of the miRNA studied, whether the miRNA was shown to affect multiple cell types (pleiotropy), which cell types were studied, and the physiologic process that the miRNA was shown to target. The numbers following each division represents the number of studies that is in that category.

Fig. 3.. Summary of miRNAs that target cardiomyocytes after MI.

miRNAs have been shown to regulate apoptosis, necrosis, and autophagy-mediated cardiomyocyte cell death. For cardiomyocyte proliferation, miRNAs have been shown to modulate multiple proliferative pathways as well as the cell cycle directly. Last, miRNAs have also been shown to regulate important processes including hypertrophy, arrhythmia, and inflammation. Select well-characterized miRNAs, their targets (written above the arrows), and the processes that they regulate are shown (i.e., miR-19b prevents apoptosis through BIM signaling). miRNAs prefaced with “anti-” denote that the inhibition of the miRNA is therapeutic (i.e., the inhibition of miR-1 prevents apoptosis through BCL-2 signaling). For the complete list of miRNAs reviewed that affect cardiomyocytes, please see table S1.

Fig. 4.. Summary of miRNAs that target fibroblasts, endothelial cells, and immune cells.

(A) In CFs, miRNAs can regulate TGFβ signaling as well as ECM synthesis and pathological proliferation. (B) In ECs, a large number of miRNAs have been shown to regulate angiogenesis, whereas others have been shown to regulate EC apoptosis. (C) In immune cells, miRNAs can regulate multiple aspects of macrophage function including immune cell infiltration, cytokine production, macrophage polarization, efferocytosis, and phagocytosis, as well as angiogenesis signal release. Select well-characterized miRNAs, their targets (written above the arrows), and the processes that they regulate are shown (i.e., miR-24 prevents TGFβ activation through FURIN signaling). miRNAs prefaced with anti–denote that the inhibition of the miRNA is therapeutic (i.e., the inhibition of miR-433 prevents TGFβ activation through AZIN1 signaling). For the complete list of miRNAs reviewed, please see table S1.