PMID- 30355233 OWN - NLM STAT- MEDLINE DCOM- 20191007 LR - 20220129 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 123 IP - 6 DP - 2018 Aug 31 TI - miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy. PG - 673-685 LID - 10.1161/CIRCRESAHA.118.312751 [doi] AB - RATIONALE: Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown. OBJECTIVE: To examine miR-146a-mediated SUMO1 regulation and its consequent effects on cardiac morphology and function. METHODS AND RESULTS: In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a-producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle-associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility. CONCLUSIONS: Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention. FAU - Oh, Jae Gyun AU - Oh JG AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Watanabe, Shin AU - Watanabe S AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Lee, Ahyoung AU - Lee A AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Gorski, Przemek A AU - Gorski PA AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Lee, Philyoung AU - Lee P AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Jeong, Dongtak AU - Jeong D AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Liang, Lifan AU - Liang L AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Liang, Yaxuan AU - Liang Y AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Baccarini, Alessia AU - Baccarini A AD - Department of Genetics and Genomic Sciences (A.B., B.D.B.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York. FAU - Sahoo, Susmita AU - Sahoo S AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Brown, Brian D AU - Brown BD AD - Department of Genetics and Genomic Sciences (A.B., B.D.B.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York. FAU - Hajjar, Roger J AU - Hajjar RJ AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). FAU - Kho, Changwon AU - Kho C AD - From the Department of Cardiology, Cardiovascular Research Center (J.G.O., S.W., A.L., P.A.G., P.L., D.J., L.L., Y.L., S.S., R.J.H., C.K.). LA - eng GR - 17POST33410877/AHA/American Heart Association-American Stroke Association/United States GR - R01 HL131404/HL/NHLBI NIH HHS/United States GR - P50 HL112324/HL/NHLBI NIH HHS/United States GR - R01 HL119046/HL/NHLBI NIH HHS/United States GR - R01 HL128099/HL/NHLBI NIH HHS/United States GR - R01 HL117505/HL/NHLBI NIH HHS/United States GR - R00 HL116645/HL/NHLBI NIH HHS/United States GR - T32 HL007824/HL/NHLBI NIH HHS/United States GR - R01 HL135093/HL/NHLBI NIH HHS/United States GR - K99 HL116645/HL/NHLBI NIH HHS/United States GR - R01 HL129814/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (MIRN146 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Mirn146 microRNA, mouse) RN - 0 (SUMO-1 Protein) RN - 0 (SUMO1 protein, human) RN - 0 (Sumo1 protein, mouse) SB - IM MH - Animals MH - Cardiomegaly/genetics/*metabolism/pathology/physiopathology MH - Cell Communication MH - Cell Transdifferentiation MH - Cells, Cultured MH - Disease Models, Animal MH - Down-Regulation MH - Fibroblasts/metabolism/pathology MH - Heart Failure/genetics/*metabolism/pathology/physiopathology MH - Humans MH - Male MH - Mice MH - MicroRNAs/genetics/*metabolism MH - *Myocardial Contraction MH - Myocytes, Cardiac/*metabolism/pathology MH - SUMO-1 Protein/genetics/*metabolism MH - Signal Transduction MH - Sumoylation PMC - PMC6205728 MID - NIHMS1503077 OTO - NOTNLM OT - extracellular vesicle OT - heart failure OT - mice OT - microRNA OT - sarcoplasmic reticulum EDAT- 2018/10/26 06:00 MHDA- 2019/10/08 06:00 PMCR- 2019/08/31 CRDT- 2018/10/26 06:00 PHST- 2018/10/26 06:00 [entrez] PHST- 2018/10/26 06:00 [pubmed] PHST- 2019/10/08 06:00 [medline] PHST- 2019/08/31 00:00 [pmc-release] AID - 10.1161/CIRCRESAHA.118.312751 [doi] PST - ppublish SO - Circ Res. 2018 Aug 31;123(6):673-685. doi: 10.1161/CIRCRESAHA.118.312751.