Abstract
MicroRNAs (miRNAs) are short, noncoding RNAs that regulate post-transcriptional gene expression by targeting messenger RNAs (mRNAs) for cleavage or translational repression. Growing evidence indicates that miR-155 expression changes with the development of heart and plays an important role in heart physiopathology. However, the role of miR-155 in cardiac cells differentiation is unclear. Using the well-established embryonic stem cell (ESC), we demonstrated that miR-155-3p expression was down-regulated during cardiogenesis from mouse ESC. By contrast, the myogenic enhance factor 2C (MEF2C), a predicted target gene of miR-155-3p, was up-regulated. We further demonstrated that miR-155-3p inhibition increased the percentage of embryoid bodies (EB) beating and up-regulated the expression of cardiac specific markers, GATA4, Nkx2.5, and cTnT mRNA and protein. Notably, miR-155-3p inhibition caused upregulation of MEF2C, KRAS and ERK1/2. ERK1/2 inhibitor, PD98059 significantly decreased the expression of MEF2C protein. These findings indicate that miR-155-3p inhibition promotes cardiogenesis, and its mechanisms are involved in the RAS-ERK1/2 signaling and MEF2C.
Highlights
Heart disease, including myocardial infarction, is the leading cause of death worldwide
These findings indicate that miR-155-3p inhibition promotes cardiogenesis, and its mechanisms are involved in the RAS-ERK1/2 signaling and myogenic enhance factor 2C (MEF2C)
The present study demonstrated the following novel findings: (1) miR-155-3p was down-regulated during embryonic stem cell (ESC) differentiation. (2) miR-155-3p mimic attenuated MEF2C expression in embryoid bodies (EB). (3) miR-155-3p inhibition increased MEF2C, KRAS, and pERK1/2 expression
Summary
Heart disease, including myocardial infarction, is the leading cause of death worldwide. Stem cell therapies have been investigated as a possible treatment approach for cardiac disease [2,3,4]. MiR-590 and miR-199a are shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and enhance the cardiomyocyte proliferation. They stimulated marked cardiac regeneration and almost recovered cardiac functional parameters in a mouse myocardial infarction model [17]. MicroRNA promoted cardiac progenitor cell proliferation and differentiation and facilitated the ESCs to differentiate into cardiomyocyte, which can potentially increase the efficiency stem cell therapy in cardiac diseases. Our novel understanding of the miR155-3p inhibition in cardiogenesis could partly enlighten a new therapeutic strategy to heart disease
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