Molecular Biological Mechanism Of LncRNA PHAT-mediated Exercise-induced Physiological Cardiac Hypertrophy

Aims: Exercise training can induce cardiac physiological hypertrophy,promote cardiomyocytes proliferation,and play a protective role in pathological cardiac hypertrophy and ventricular remodeling.Previous studies have revealed a series pathological cardiac hypertrophy related noncoding RNAs and illuminated their molecular mechanisms.However,physiologic hypertrophy associated long noncoding RNAs(lnc RNAs)still remain unclear.Therefore,this study aims to investigate the role of lnc RNAs involved in exercise induced cardiac physiologic hypertrophy and to demonstrate the underlying molecular mechanism.Methods and Results: Expression of the lnc RNAs was determined by chip screening tests in heart samples from 8 week-old mice after 3-weeks of forced swimming training,and we found that lnc RNA PHAT was upregulated.Fluorescence in situ hybridization(FISH)and RT-PCR analyses validated that both nucleus and cytoplasm has certain expression of lnc RNA PHAT.In isolated neonatal mice cardiomyocytes,forcedexpression of lnc RNA PHAT induced cardiomyocytes hypertrophy and proliferation as determined by EDU or Ki-67 staining and cell number counting.Besides,increased expression of lnc RNA PHAT could protect cardiomyocytes from apoptosis induced by ischemia reperfusion(OGD/R).In order to disclose the biological mechanisms of lnc RNA PHAT,we screened 26 related genes according to the gene chip results by RTPCR and found that transcriptional activation factor 7(ATF7)was decreased when lnc RNA PHAT over-expressed.Loss-and gain-of-function experiments showed that ATF7 was a target gene of lnc RNA PHAT.In vivo,downregulation of lnc RNA PHAT can inhibit exercise-induced cardiac physiological hypertrophy and cardiomyocytes proliferation.Meanwhile,lnc RNA PHAT overexpression adeno-associated virus delivered 1 week before ischemia-reperfusion injury showed less impairment of cardiac function and fibrosis.Conclusions: Lnc RNA PHAT is necessary for exercise-induced cardiac physiological hypertrophy and protects against adverse remodeling after myocardial ischemiareperfusion injury.Lnc RNA PHAT may a promising therapeutic target to promote functional recovery after ischemia-reperfusion.