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

Venkata N.S. Garikipati, Suresh K. Verma, Darukeshwara Jolardarashi, Zhongjian Cheng, Jessica Ibetti, Maria Cimini, Yan Tang, Mohsin Khan, Yujia Yue, Cindy Benedict, Emily Nickoloff, May M. Truongcao, Erhe Gao, Prasanna Krishnamurthy, David A. Goukassian, Walter J. Koch, Raj Kishore

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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-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.

Original languageEnglish
Pages (from-to)938-949
Number of pages12
JournalCardiovascular Research
Volume113
Issue number8
DOIs
StatePublished - 1 Jul 2017
Externally publishedYes

Keywords

  • Cardiac repair
  • Inflammation
  • MiRNA
  • Myocardial infarction

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