Abstract 12433: miR 187a-3p Prevents Septic-Induced Myocardial Dysfunction by Targeting the Inflammatory Cytokines TNFa and IL-6

Abstract

Introduction: Patients with severe, sepsis can develop acute heart failure characterized by left ventricular dilatation and decreased contractility. Inflammatory mediators, including TNFα, IL-6 and IL-1β contribute to the activation of inflammation and ventricular remodeling. Therapeutic interventions for sepsis are lacking. Previously, we demonstrated that miR187-3p, a regulator of TNFα is dysregulated in the septic heart, in a pre-clinical model of sepsis. Hypothesis: We hypothesize that administering miR187-3p mimic would reduce inflammatory cytokine production and improve cardiac function and mortality rate. Methods: Polymicrobial sepsis was induced in mice via cecal ligation and perforation (CLP) surgery, mice undergoing sham surgery served as controls. MiR187-3p mimic, miRNA negative control, or saline were administered IV 6 hrs post-CLP. At 48 hrs post-CLP, following echocardiographic and hemodynamic assessments, the mice were sacrificed, and the hearts collected for biochemical, and molecular analysis. To complement the experimental findings, autopsy human hearts and circulatory blood samples from septic patients and healthy controls were collected and the expression of miR187a-3p and inflammatory cytokines were analyzed. Results: Administration of miR-187-3p mimic to septic mice 6 hrs post-CLP increased survival, improved echo-derived indices of cardiac function (left ventricular ejection fraction, fractional shortening), increased bacterial clearance and reduced inflammation when compared to septic mice receiving a scrambled control miR. In septic mice, miR-187-3p expression decreased in both the circulation and heart tissue. In addition to TNFα, bioinformatic analysis, confirmed by luciferase assays, identified IL-6 as a specific target of miR187-3p in cardiac myocytes. In septic patients, the expression of miR-187-3p and target inflammatory cytokines decreased in plasma and autopsied hearts. Conclusions: Delivery of miR-187-3p improves outcomes in sepsis-induced myocardial dysfunction. Thus, miR-187-3p serves as a potential biomarker and therapeutic target for prevention and prognostic reflection in sepsis-induced myocardial dysfunction.