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Cardiovasc Res. 2017 Jul 1;113(8):938-949. doi: 10.1093/cvr/cvx052.

Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis.

Author information

1
Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
2
Department of Biomedical Engineering, University of Alabama at Birmingham, 1675 University Blvd., Volker Hall G094, Birmingham, AL 35294, USA.
3
Department of Pharmacology, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.

Abstract

Aims:

Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whether inhibition of MI-induced miR-375 by LNA anti-miR-375 can improve recovery after acute MI.

Methods and results:

Ten weeks old mice were treated with either control or LNA anti miR-375 after induction of MI by LAD ligation. The inflammatory response, cardiomyocyte apoptosis, capillary density and left ventricular (LV) functional, and structural remodelling changes were evaluated. Anti-miR-375 therapy significantly decreased inflammatory response and reduced cardiomyocyte apoptosis in the ischemic myocardium and significantly improved LV function and neovascularization and reduced infarct size. Repression of miR-375 led to the activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and increased AKT phosphorylation on Thr-308 in experimental hearts. In corroboration with our in vivo findings, our in vitro studies demonstrated that knockdown of miR-375 in macrophages modulated their phenotype, enhanced PDK-1 levels, and reduced pro-inflammatory cytokines expression following LPS challenge. Further, miR-375 levels were elevated in failing human heart tissue.

Conclusion:

Taken together, our studies demonstrate that anti-miR-375 therapy reduced inflammatory response, decreased cardiomyocyte death, improved LV function, and enhanced angiogenesis by targeting multiple cell types mediated at least in part through PDK-1/AKT signalling mechanisms.

KEYWORDS:

Cardiac repair; Inflammation; MiRNA; Myocardial infarction

PMID:
28371849
DOI:
10.1093/cvr/cvx052
[Indexed for MEDLINE]

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