Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits K ATP channels through CaMKII activation
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RESEARCH
Open Access
Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation Yanzhuo Ma1,2, Nancy Cheng2, Junping Sun2, Jonathan Xuhai Lu3,4, Shahrzad Abbasi5, Geru Wu2, An-Sheng Lee6,7, Tatsuya Sawamura8,9, Jie Cheng2, Chu-Huang Chen3,8* and Yutao Xi1,10*
Abstract Background: Cardiac Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (KATP) 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 KATP 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/gp91phox. The function of KATP 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 KATP current (IKATP) density induced by pinacidil, a KATP opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the IKATP blocker glibenclamide. Suppression of IKATP by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91phox. 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. Keywords: Action potential, ATP-sensitive potassium, Ca2+/calmodulin-dependent protein kinase II, Cardiomyocytes, Electronegative low-density lipoprotein
* Correspondence: [email protected]; [email protected] 3 Vascular and Medicinal Research, Texas Heart Institute, 6770 Bertner Avenue, Houston, TX 77030, USA 1 Department of Cardiology, Bethune International Peace Hospital, 398 Zhongshan Xilu, Shijiazhuang 050082, Hebei, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any
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