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고창원 (Changwon Kho) 저자 이메일 보기
Icahn School of Medicine at Mount Sinai
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조회 367  인쇄하기 주소복사 트위터 공유 페이스북 공유 
miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy
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Abstract
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 Ca2+-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.

Key Words: extracellular vesicle, heart failure, mice, microRNA, sarcoplasmic reticulum
논문정보
- 형식: Research article
- 게재일: 2018년 08월 (BRIC 등록일 2018-08-31)
- 연구진: 국외연구진
- 분야: Medicine
세포 형광 이미징 멀티플렉싱을 위한 초고속 사이클링[Angew. Chem.-Int. Edit.]
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발표: 고진아 (Massachusetts General Ho...)
일자: 2020년 4월 14일 (화) 오전 10시 (한국시간)
언어: 영어
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오재균 (Icahn School of...)
이아영 (Mount Sinai Sch...)
장승필 (Bethphagen inc)
정동탁 (Icahn School of...)
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