Mir-21 Contributes to Cardiac Aging by Targeting Pten

Background— Aging is among predominant risk factors for cardiovascular diseases and it also contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs, miRs) have been indicated in aging. However, the regulatory mechanisms of miRNAs which govern the aging progress are poorly understood. Objective— To identify miRNAs responsible for cardiac aging besides miR-34 family members. Methods and Results— miRNA arrays were used to determine the dysregulated miRNAs in cardiac aging using cardiac ventricles from mice at 8 weeks and 15months of age. Besides miR-34 family members, miR-21 was also found to be elevated 3-fold in ventricles from mice aged 15 months compared to mice aged 8 weeks. Over-expression of miR-21 in the neonatal rat cardiomyocytes (NRCM) shortened the telomere length, attenuated and strengthened the activity of telomerase and senescence-related beta[[Unable to Display Character: –]]galactosidase, respectively, which was similar to the aging caused by doxorubicin (DOX). Using the quantitative PCRs and Western blotting, phosphatase and tensin homologue (PTEN) gene was found to be negatively regulated by miR-21 in NRCM. Moreover, knockdown of PTEN using siRNA mimics the effects of miR-21 in pro-aging in NRCM. Interestingly, knockdown of miR-21, as well as up-regulation of PTEN, repressed NRCM aging induced by DOX. Conclusions— These findings suggest that ectopic up- or down-modulation of miR-21 may be an important regulatory mechanism governing cardiac aging by targeting PTEN. Inhibition of miR-21 represent a novel therapy for cardiac aging.