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.
Highlights
One of the immediate consequences of cardiac injury is cell death
left ventricles (LVs) slices were stained in 1.5% triphenyltetrazolium chloride (TTC) for 30 min. at 37°C, and fixed in 4% PFA overnight at 4°C
It has been demonstrated that miR-24 plays a role in a variety of cell types in the heart, including cardiomyocytes [24, 36], fibroblasts [29], as well as endothelial cells [30]
Summary
One of the immediate consequences of cardiac injury is cell death. The massive death of the contractile muscle cells is followed by scar formation, dysfunction of the heart and heart failure. Because the human heart has a limited regenerative capacity, preventing the loss of existing cells and promoting the generation of new cardiomyocytes are current approaches being extensively studied. Recent advances in direct cardiac reprogramming introduce a new possibility of regenerating the heart by converting endogenous cardiac fibroblasts (CFs) or other fibroblasts into cardiomyocyte-like cells (mouse, [2,3,4,5,6]; human, [7,8,9]). The potential to utilize a large pool of endogenous CFs to generate functional cardiomyocytes points to a promising avenue to repairing the damaged myocardium in human patients. The fact remains that most of the reprogrammed CFs do not become fully matured, and that in vivo reprogramming has only worked far when the reprogramming factors (such as Gata, Mef2c and Tbx (GMT) in mice) are introduced at the time of injury
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