Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart.

Md Kamrul Hasan Chowdhury,Ademuyiwa S Aromolaran,Kelly A Aromolaran,Laura Martinez-Mateu,Jenny Do,Javier Saiz

doi:10.3390/ijms222011249

Md Kamrul Hasan Chowdhury, Ademuyiwa S Aromolaran + Show 4 more

Open Access

https://doi.org/10.3390/ijms222011249

Copy DOI

Abstract

In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.

Highlights

Dietary obesity is a major contributor to the increasing prevalence of cardiovascular diseases worldwide [1]
We assessed the ability of the saturated free fatty acid, palmitic acid (PA, an inducer of lipotoxicity) to induce pro-inflammatory cytokine release in RAW264.7 macrophage cells
We examined the effect of IL-6 in combination with the IL-6R directly on cardiomyocyte function and determined whether adverse ventricular electrical remodeling occurred in the presence of IL-6 + IL-6R

Summary

Introduction

Dietary obesity is a major contributor to the increasing prevalence of cardiovascular diseases worldwide [1]. The pathology of obesity-related heart diseases [2,3,4,5,6] is associated with cardiac lipotoxicity (or the abnormal accumulation of free fatty acids, FFAs), and enhanced infiltration of activated macrophages. This macrophage activation triggers an increase in the secretion of pro-inflammatory cytokines including interleukin-6 (IL-6), tumor-necrosis factor-alpha (TNF-α), and interleukin-1 (IL-1β) [7,8].

Objectives

Methods

Results

Conclusion