MicroRNA-17-3p Promotes Physiological Cardiac Growth And Protects Cardiac Ischemia-reperfusion Injury

Aims:miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling.However,the role of other miRNAs in this process is unclear.This study investigated the role of members of the miR-17-92 cluster and their passenger miRNAs in exercise-induced cardiac growth.Methods and Results:Expression of the miR-17-92 cluster including miR-17-5p,-18a-5p,-19a-5p,-20a-5p,-19b-1-5p and-92a-5p and their passenger miRNAs,(miR-17-3p,-18a-3p,-19a-3p,-19b-3p,-20a-3p and-92a-3p)was determined by quantitative reverse transcription polymerase chain reactions(RT-PCRs)in heart samples from mice after 3-weeks of swimming training.miR-17-3p and miR-18a-3p were found to be increased in the murine swimming model,while only miR-17-3p was also increased in a voluntary wheel running model.Interestingly,miR-17-3p was decreased in ventricular tissues of dilated cardiomyopathy(DCM)patients and mice after transverse aortic constriction(TAC).Importantly,the increase of miR-17-3p is specifically in cardiomyocytes in vivo.In isolated cardiomyocytes,forced-expression of miR-17-3p induced cardiomyocyte hypertrophy and proliferation as determined by EdU or Ki-67 staining and cell number.Tissue inhibitor of metalloproteinase 3(TIMP3)was identified as a direct target gene of miR-17-3p,which contributes to cardiomyocyte proliferation.miR-17-3p was also found to indirectly inhibit PTEN and thereby activate Akt,contributing to cardiomyocyte hypertrophy.In vivo,inhibition of miR-17-3p inhibited exercise-induced cardiac growth and markers of cardiomyocyte proliferation.Conversely,miR-17-3p agomir delivered 24 hr after ischemia-reperfusion injury showed less cardiomyocyte apoptosis,impairment of cardiac function,and fibrosis,as well as increased markers of cardiomyocyte proliferation.Conclusions:miR-17-3p contributes to exercise-induced cardiac growth and protects against adverse remodeling after myocardial ischemia-reperfusion injury.miR-17-3p may represent a novel therapeutic target to promote functional recovery after ischemia-reperfusion.