Overexpression of microRNA-1 impairs cardiac contractile function by damaging sarcomere assembly.
OBJECTIVE
The purpose of the present study was to evaluate the effects of overexpression of microRNA-1 (miR-1) on cardiac contractile function and the potential molecular mechanisms.


RESULTS
Transgenic (Tg) mice (C57BL/6) for cardiac-specific overexpression of miR-1 driven by the α-myosin heavy chain promoter were generated and identified by real-time reverse-transcription polymerase chain reaction with left ventricular samples. We found an age-dependent decrease in the heart function in Tg mice by pressure-volume loop analysis. Histological analysis and electron microscopy displayed short sarcomeres with the loss of the clear zone and H-zone as well as myofibril fragmentation and deliquescence in Tg mice. Further studies demonstrated miR-1 post-transcriptionally down-regulated the expression of calmodulin (CaM) and cardiac myosin light chain kinase (cMLCK) proteins by targeting the 3'UTRs of MYLK3, CALM1, and CALM2 genes, leading to decreased phosphorylations of myosin light chain 2v (MLC2v) and cardiac myosin binding protein-C (cMyBP-C). Knockdown of miR-1 by locked nucleic acid-modified anti-miR-1 antisense (LNA-antimiR-1) mitigated the adverse changes of cardiac function associated with overexpression of miR-1.


CONCLUSIONS
miR-1 induces adverse structural remodelling to impair cardiac contractile function. Targeting cMLCK and CaM likely underlies the detrimental effects of miR-1 on structural components of muscles related to the contractile machinery. Our study provides the first evidence that miRNAs cause adverse structural remodelling of the heart.
Department of Pharmacology , Harbin Medical University, No. 157 Baojian Road, Nangang District, Harbin, China. a.z.hrbmu@gmail.com
Jing
J
Ai
Rong
R
Zhang
Xu
X
Gao
Hui-Fang
HF
Niu
Ning
N
Wang
Yi
Y
Xu
Yue
Y
Li
Ning
N
Ma
Li-Hua
LH
Sun
Zhen-Wei
ZW
Pan
Wei-Min
WM
Li
Bao-Feng
BF
Yang
D020413:3' Untranslated Regions; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000235:genetics; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000378:metabolism* / Q000648:ultrastructure; D015854:Up-Regulation; D016276:Ventricular Function; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling
D020413:3' Untranslated Regions; D002147:Calmodulin; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D009219:Myosin-Light-Chain Kinase; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains