Mir-21-Mediated Decreased Neutrophil Apoptosis Is a Determinant of Impaired Coronary Collateral Growth in Metabolic Syndrome

Authors

Rebecca Hutcheson, Department of Pharmacology, New York Medical College, Valhalla, New York;
Russell Terry, Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
Brenda Hutcheson, Department of Pharmacology, New York Medical College, Valhalla, New York;
Rashmi Jadhav, Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
Jennifer Chaplin, Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
Erika Smith, Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama;
Robert Barrington, Department of Microbiology and Immunology, University of South Alabama College of Medicine, Mobile, Alabama; and.
Spencer D. Proctor, Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada.
Petra Rocic, Department of Pharmacology, New York Medical College, Valhalla, New York; petra_rocic@nymc.edu.

Author Type(s)

Faculty

DOI

10.1152/ajpheart.00654.2014

Journal Title

American Journal of Physiology. Heart and Circulatory Physiology

First Page

H1323

Last Page

35

Document Type

Article

Publication Date

6-1-2015

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.

Recommended Citation

Hutcheson, R., Terry, R., Hutcheson, B., Jadhav, R., Chaplin, J., Smith, E., Barrington, R., Proctor, S. D., & Rocic, P. (2015). Mir-21-Mediated Decreased Neutrophil Apoptosis Is a Determinant of Impaired Coronary Collateral Growth in Metabolic Syndrome. American Journal of Physiology. Heart and Circulatory Physiology, 308 (11), H1323-35. https://doi.org/10.1152/ajpheart.00654.2014