Atherogenic L5 LDL Induces Cardiomyocyte Apoptosis and Inhibits K Channels Through CaMKII Activation

Overview

Journal Lipids Health Dis

Publisher Biomed Central

Specialties Biochemistry
Endocrinology

Date 2020 Aug 23

PMID 32825832

Citations 5

Authors

Yanzhuo Ma

Nancy Cheng

Junping Sun

Jonathan Xuhai Lu

Shahrzad Abbasi

Geru Wu

An-Sheng Lee

Tatsuya Sawamura

Jie Cheng

Chu-Huang Chen

Yutao Xi

Affiliations

Soon will be listed here.

Abstract

Background: Cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (K) channels are essential for cardiac protection during ischemia. In cultured CMs, L5 low-density lipoprotein (LDL) induces apoptosis and QTc prolongation. L5 is a highly electronegative and atherogenic aberrant form of LDL, and its levels are significantly higher in patients with cardiovascular-related diseases. Here, the role of L5 in cardiac injury was studied by evaluating the effects of L5 on CaMKII activity and K channel physiology in CMs.

Methods: Cultured neonatal rat CMs (NRCMs) were treated with a moderate concentration (ie, 7.5 μg/mL) of L5 or L1 (the least electronegative LDL subfraction). NRCMs were examined for apoptosis and viability, CaMKII activity, and the expression of phosphorylated CaMKIIδ and NOX2/gp91. The function of K and action potentials (APs) was analyzed by using the patch-clamp technique.

Results: In NRCMs, L5 but not L1 significantly induced cell apoptosis and reduced cell viability. Furthermore, L5 decreased Kir6.2 expression by more than 50%. Patch-clamp analysis showed that L5 reduced the K current (I) density induced by pinacidil, a K opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the I blocker glibenclamide. Suppression of I by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91. L5-induced apoptosis was prevented by the addition of the CaMKII inhibitor KN93 and the reactive oxygen species scavenger Mn (III)TBAP.

Conclusions: L5 but not L1 induces CM damage through the activation of the CaMKII pathway and increases arrhythmogenicity in CMs by modulating the AP duration. These results help to explain the harmful effects of L5 in cardiovascular-related disease.

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