Oxidized Low-Density Lipoprotein Associates with Ventricular Stress in Young Adults and Triggers Intracellular Ca2+ Alterations in Adult Ventricular Cardiomyocytes.

Elena Rodríguez-Sánchez,Sara Vázquez-Sánchez,Gloria Álvarez-Llamas,Nerea Corbacho-Alonso,Eva Calvo-Bonacho,Luis M Ruilope,Laura González-Lafuente,Jonay Poveda,Jennifer Aceves-Ripoll,María Fernández-Velasco,José Alberto Navarro-García,María G Barderas,Elisa Mercado-García,Gema Ruiz-Hurtado

doi:10.3390/antiox9121213

Abstract

Oxidized low-density lipoprotein (oxLDL) is associated with cardiac damage and causes injury to multiple cell types. We aimed to investigate the role of oxLDL in ventricular stress. We first examined the association between circulating oxLDL and N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stress, in young subjects (30–50 years) with or without stable coronary artery disease (SCAD). oxLDL and NT-proBNP were significantly higher in subjects at high cardiovascular risk (CVR) than in subjects at low CVR and were associated independently of traditional CVR factors and C-reactive protein. Furthermore, the levels of oxLDL and NT-proBNP were significantly lower in subjects with SCAD than in peers at high CVR. To determine the intracellular mechanisms involved in the cardiac effects of oxLDL, we analyzed the in vitro effect of oxLDL on intracellular Ca2+ handling in adult rat ventricular cardiomyocytes using confocal microscopy. Acute challenge of adult ventricular cardiomyocytes to oxLDL reduced systolic Ca2+ transients and sarcoplasmic reticulum Ca2+ load. Moreover, diastolic spontaneous Ca2+ leak increased significantly after acute exposure to oxLDL. Thus, we demonstrate that oxLDL associates with NT-proBNP in young subjects, and can directly induce Ca2+ mishandling in adult ventricular cardiomyoyctes, predisposing cardiomyocytes to cardiac dysfunction and arrhythmogenicity.

Highlights

Cardiovascular disease is the leading cause of death and disability worldwide
The stable coronary artery disease (SCAD) group had lower levels of total cholesterol and low-density lipoprotein (LDL) than the low-lifetime cardiovascular risk (CVR) group (p < 0.001, p < 0.05), which is likely because all subjects with SCAD were chronically treated with statins
Our results suggest that an increase in the levels of Oxidized LDL (oxLDL) might contribute to ventricular dysfunction in individuals at high CVR before the onset of a coronary event, even from a young age, and that oxLDL predisposes cardiomyocytes to systolic Ca2+ release impairment and pro-arrhythmogenic forms of diastolic Ca2+ release as a consequence of abnormal intracellular Ca2+ cycling

Summary

Introduction

Cardiovascular disease is the leading cause of death and disability worldwide. Among cardiovascular risk (CVR) factors, one of the major contributors to atherosclerosis development and progression is raised serum levels of low-density lipoprotein (LDL) cholesterol, which can penetrate the vascular wall and accumulate in the subendothelial space. LDL is highly susceptible to oxidation in the environment of the atheromatous plaque. Oxidized LDL (oxLDL) exacerbates the atherosclerosis process by triggering pro-oxidant and pro-inflammatory pathways that lead to plaque instability through mechanisms independent of LDL [1,2]. OxLDL is causally associated with the incidence of coronary events even in the setting of moderate CVR [3,4]. Less is known about the intracellular mechanisms by which oxLDL induces deleterious cardiac effects, especially at the level of cardiomyocytes

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