Cardiomyocyte‐specific role of miR‐24 in promoting cell survival

Abstract

Cardiomyocyte cell death is a major contributing factor to various cardiovascular diseases and is therefore an important target for the design of therapeutic strategies. More recently, stem cell therapies, such as transplantation of embryonic or induced pluripotent stem (iPS) cell-derived cardiomyocytes, have emerged as a promising alternative therapeutic avenue to treating cardiovascular diseases. Nevertheless, survival of these introduced cells is a serious issue that must be solved before clinical application. We and others have identified a small non-coding RNA, microRNA-24 (miR-24), as a pro-survival molecule that inhibits the apoptosis of cardiomyocytes. However, these earlier studies delivered mimics or inhibitors of miR-24 via viral transduction or chemical transfection, where the observed protective role of miR-24 in cardiomyocytes might have partially resulted from its effect on non-cardiomyocyte cells. To elucidate the cardiomyocyte-specific effects of miR-24 when overexpressed, we developed a genetic model by generating a transgenic mouse line, where miR-24 expression is driven by the cardiac-specific Myh6 promoter. The Myh6-miR-24 transgenic mice did not exhibit apparent difference from their wild-type littermates under normal physiological conditions. However, when the mice were subject to myocardial infarction (MI), the transgenic mice exhibited decreased cardiomyocyte apoptosis, improved cardiac function and reduced scar size post-MI compared to their wild-type littermates. Interestingly, the protective effects observed in our transgenic mice were smaller than those from earlier reported approaches as well as our parallelly performed non-genetic approach, raising the possibility that non-genetic approaches of introducing miR-24 might have been mediated via other cell types than cardiomyocytes, leading to a more dramatic phenotype. In conclusion, our study for the first time directly tests the cardiomyocyte-specific role of miR-24 in the adult heart, and may provide insight to strategy design when considering miRNA-based therapies for cardiovascular diseases.

Diverse impact of xeno-free conditions on biological and regenerative properties of hUC-MSCs and their extracellular vesicles

“…5f, g). We identified significantly greater concentration of several miRNAs with pro-cardiomyogenic and cardioprotective role including miR199a-3p, miR-199a-5p [31], and miR-23a-3p [32] in M3- and M4-EVs and elevated level of miR-24a [33] in M3-EVs when compared to the control M6-EVs (Fig. 5f).…”

Bimgene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development

“…In this study, Bim expression was post‐transcriptionally modulated by miR‐17 and miR‐106b . Of the miRNAs we tested, miR10a , miR‐17 , and miR‐24–1 have been shown to regulate Bim expression in other organ systems: cardiac myocytes (53–55), pancreatic carcinoma (99), ovarian cells (52), lymphocytes (100, 101), or acute lymphocytic leukemia (56). Contrary to our findings, Kan and colleagues (57) did not detect changes in Bim expression in the presence of either the miR‐106b mimic or the miR‐106b inhibitor, probably because of differences in endogenous miRNA expression in different tissues.…”

MicroRNAs in heart failure: from biomarker to target for therapy

“…In cardiomyocytes, miR‐24 was mainly described as regulating apoptosis and cell survival via intrinsic apoptotic pathways . In transgenic miR‐24 mice undergoing MI, significantly less apoptosis and improved cardiac function was found compared with wild‐type mice . MiR‐24 was also found to have a regulatory role in excitation–contraction uncoupling of the sarcoplasmic reticulum and T‐tubules via the junctophilin‐2 protein .…”