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

Academic Article

Abstract

  • © The Author 2017. 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-phosphoinositidedependent 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.All rights reserved.
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    Author List

  • Garikipati VNS; Verma SK; Jolardarashi D; Cheng Z; Ibetti J; Cimini M; Tang Y; Khan M; Yue Y; Benedict C
  • Start Page

  • 938
  • End Page

  • 949
  • Volume

  • 113
  • Issue

  • 8