Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.
Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
van Rooij
Eva
E
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Sutherland
Lillian B
LB
Thatcher
Jeffrey E
JE
DiMaio
J Michael
JM
Naseem
R Haris
RH
Marshall
William S
WS
Hill
Joseph A
JA
Olson
Eric N
EN
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004719:Endomyocardial Fibrosis / Q000235:genetics* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger
D016326:Extracellular Matrix Proteins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D003094:Collagen