Human electronegative low-density lipoprotein modulates cardiac repolarization via LOX-1-mediated alteration of sarcolemmal ion channels

An-Sheng Lee,Kuan-Cheng Chang,Yutao Xi,Chu-Huang Chen,Hua-Chen Chan,Hsien-Yu Peng,Chin-Hu Lai,Wei-Yu Chen

doi:10.1038/s41598-017-10503-x

Abstract

Dyslipidemia is associated with greater risk of ventricular tachyarrhythmias in patients with cardiovascular diseases. We aimed to examine whether the most electronegative subfraction of low-density lipoprotein (LDL), L5, is correlated with QTc prolongation in patients with coronary artery disease (CAD) and investigate the effects of human L5 on the electrophysiological properties of cardiomyocytes in relation to the lectin-like oxidized LDL receptor (LOX-1). L5 was isolated from the plasma of 40 patients with angiography documented CAD and 13 patients with no CAD to correlate the QTc interval respectively. The mean concentration of L5 was higher and correlated with QTc in patients with CAD compared to controls. To examine the direct effect of L5 on QTc, mice were intravenously injected with L5 or L1. L5-injected wild-type but not LOX-1−/− mice showed longer QTc compared to L1-injected animals in vivo with corresponding longer action potential duration (APD) in cardiomyocytes incubated with L5 in vitro. The APD prolongation was mediated by an increase of L-type calcium current and a decrease of transient outward potassium current. We show that L5 was positively correlated with QTc prolongation in patients with ischemic heart disease. L5 can modulate cardiac repolarization via LOX-1-mediated alteration sarcolemmal ionic currents.

Highlights

Dyslipidemia, characterized by high plasma levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol is an independent risk factor for coronary artery disease and myocardial infarction[1,2,3,4]
The prevalence of established cardiovascular diseases or risk factors such as hypertension, diabetes, hyperlipidemia, cerebral vascular accident, and end-stage renal disease was comparable between patients with and with no coronary artery disease (CAD)
We demonstrate for the first time that the level of the most negatively charged subtraction of circulating lowdensity lipoprotein (LDL), L5, was positively correlated with QTc prolongation in patients with coronary artery disease

Summary

Introduction

Dyslipidemia, characterized by high plasma levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol is an independent risk factor for coronary artery disease and myocardial infarction[1,2,3,4]. A recent meta-analysis showed that reducing LDL cholesterol with a statin was associated with a lower risk of sudden cardiac death, but not the risk of ventricular tachyarrhythmias[16]. All these lines of clinical evidence suggest that dyslipidemia www.nature.com/scientificreports/. We correlated the plasma L5 level with the electrocardiographic QTc variation in patients with coronary artery disease (CAD) and examined the electrophysiological properties of isolated cardiomyocytes from both wild type and LOX-1 knockout mice (LOX-1−/−) to delineate the role of LOX-1 involved in the L5-mediated electrical remodeling in cardiomyocytes

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