Abstract 3550: Overexpression Of Mir-21 Delays The Onset Of Cardiac Failure
MicroRNAs (miRNAs) are posttranscriptional regulators that are differentially regulated during cardiac hypertrophy, recapitulating the neonatal pattern. MiRNA-21 is one of the most prominent miRNA identified in cardiac hypertrophy and cancer. During compensatory cardiac hypertrophy it increases up to 8 fold then starts declining with the onset of decompensation. Recently, a unique role of miR-21 has been described in cardiac myocytes where it induces cellular outgrowths in the form of extension that connect adjacent cells via functional gap junctions mediated through downregulation of Sprouty2. Other studies have shown conflicting pro- versus anti-hypertrophic effects of miR-21 in myocytes. To conclusively determine the significance of the upregulation of miR-21 in the heart in vivo, we generated a mouse with a myosin heavy chain-driven miR-21 transgene. Up to 10 months of age the transgenic hearts exhibit normal physical and functional parameters and was negative for hypertrophy markers. This refuted the claim that miR-21 is sufficient for induction of cardiac hypertrophy. To address whether miR-21 was anti-hypertrophic we subjected 12 wk old mice to transverse aortic banding for various time periods. During the early phases the extent of increase in cardiac mass was not significantly different from wild type. But interestingly at the later stages of hypertrophy, while the wild type progressed into contractile dysfunction, the miR-21 transgenic lines had normal ejection fraction and left ventricular end diastolic pressure. This suggested that miR-21 upregulation is not anti-hypertrophic but rather conferred contractile and/or survival advantages to the cardiac myocytes. Consistent with the previously described role of miR-21 and with the remodeling of connexin43 (Cx43) associated with compensatory hypertrophy, the myocytes exhibited frequent lateralization of Cx43 that coincided with lateral connecting extensions between myocytes. This distribution of Cx43 known to be associated with hypertrophy is reversed during failure, which coincides with the return of miR-21 to baseline levels. Thus, we propose that overexpressing miR-21 at that juncture provides a functional advantage to the heart coping with chronic pressure overload.