title: miR-21 normalizes vascular smooth muscle proliferation and improves coronary collateral growth in metabolic syndrome.
abstract: Inadequate cell proliferation is considered a major causative factor for impaired coronary collateral growth (CCG). Proangiogenic growth factors (GFs) stimulate cell proliferation, but their administration does not promote CCG in patients. These GFs are increased in patients with metabolic syndrome and in animal models, where CCG is impaired. Here, we investigated whether excessive cell proliferation underlies impaired CCG in metabolic syndrome. Normal [Sprague-Dawley (SD)] and metabolic syndrome [James C. Russell (JCR)] rats underwent repetitive ischemia (RI; transient, repetitive coronary artery occlusion and myocardial ischemia). We have shown that CCG was maximal at d 9 of RI in SD rats but did not occur in JCR rats. The increase in cell proliferation (PCNA, Ki-67, cyclin A, phospho- cdc2, p21Waf, p27Kip) was transient (∼4-fold, d 3 RI) in SD rats but greater and sustained in JCR rats (∼8- to 6-fold, d 3-9 RI). In JCR rats, this was associated with increased and sustained miR-21 expression and accumulation of proliferating synthetic vascular smooth muscle cells in the lumen of small arterioles, which failed to undergo outward expansion. Administration of anti-miR-21 blocked RI-induced cell proliferation and significantly improved CCG in JCR rats (∼60%). miR-21-dependent excessive cell proliferation in the later stages of collateral remodeling correlates with impaired CCG in metabolic syndrome.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hutcheson
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chaplin
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA;
authors.forename: Brenda
authors.initials: B
authors.lastname: Hutcheson
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Faye
authors.initials: F
authors.lastname: Borthwick
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Spencer
authors.initials: S
authors.lastname: Proctor
authors.affiliation: Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama, USA; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gebb
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Jadhav
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Erika
authors.initials: E
authors.lastname: Smith
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Russell
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA; petra_rocic@nymc.edu.
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000502:physiology*; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003326:Coronary Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D008297:Male; D024821:Metabolic Syndrome / Q000503:physiopathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C546082:mirn21 microRNA, rat
keywords: arteriogenesis; cell cycle; insulin resistance; molecular mechanisms; transient repetitive ischemia