title: MicroRNA-26a is a novel regulator of vascular smooth muscle cell function.
abstract: Aberrant smooth muscle cell (SMC) plasticity has been implicated in a variety of vascular disorders including atherosclerosis, restenosis, and abdominal aortic aneurysm (AAA) formation. While the pathways governing this process remain unclear, epigenetic regulation by specific microRNAs (miRNAs) has been demonstrated in SMCs. We hypothesized that additional miRNAs might play an important role in determining vascular SMC phenotype. Microarray analysis of miRNAs was performed on human aortic SMCs undergoing phenotypic switching in response to serum withdrawal, and identified 31 significantly regulated entities. We chose the highly conserved candidate miRNA-26a for additional studies. Inhibition of miRNA-26a accelerated SMC differentiation, and also promoted apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunted differentiation. As a potential mechanism, we investigated whether miRNA-26a influences TGF-β-pathway signaling. Dual-luciferase reporter assays demonstrated enhanced SMAD signaling with miRNA-26a inhibition, and the opposite effect with miRNA-26a overexpression in transfected human cells. Furthermore, inhibition of miRNA-26a increased gene expression of SMAD-1 and SMAD-4, while overexpression inhibited SMAD-1. MicroRNA-26a was also found to be downregulated in two mouse models of AAA formation (2.5- to 3.8-fold decrease, P < 0.02) in which enhanced switching from contractile to synthetic phenotype occurs. In summary, miRNA-26a promotes vascular SMC proliferation while inhibiting cellular differentiation and apoptosis, and alters TGF-β pathway signaling. MicroRNA-26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. nleeper@stanford.edu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
mesh_terms: D000783:Aneurysm / Q000235:genetics / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016895:Culture Media, Serum-Free; D035683:MicroRNAs; D051898:Smad1 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C528163:MIRN26 microRNA, human; C543693:Mirn26 microRNA, mouse