title: miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome.
abstract: Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome-c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (~50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (~75%) while increasing Bax/Bax dimers, cytochrome-c release, and caspase activation (~70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (~60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hutcheson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
authors.forename: Russell
authors.initials: R
authors.lastname: Terry
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Brenda
authors.initials: B
authors.lastname: Hutcheson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
authors.forename: Rashmi
authors.initials: R
authors.lastname: Jadhav
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chaplin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
authors.forename: Erika
authors.initials: E
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, University of South Alabama College of Medicine, Mobile, Alabama; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Barrington
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Proctor
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; petra_rocic@nymc.edu.
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D054059:Coronary Occlusion / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045304:Cytochromes c / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C546082:mirn21 microRNA, rat; D045304:Cytochromes c
keywords: apoptosis; collateral circulation; inflammation; metabolic syndrome; microRNA
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