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. 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. 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. 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.

中文翻译：

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致动脉粥样硬化性L5 LDL诱导心肌细胞凋亡，并通过CaMKII激活抑制KATP通道。

心脏Ca2 + /钙调蛋白依赖性蛋白激酶II（CaMKII）的激活在心肌细胞（CM）凋亡和心律不齐中起关键作用。功能性ATP敏感性钾（KATP）通道对于缺血期间的心脏保护至关重要。在培养的CM中，L5低密度脂蛋白（LDL）诱导细胞凋亡和QTc延长。L5是LDL的高度电负性和动脉粥样硬化异常形式，在患有心血管相关疾病的患者中其水平明显更高。在这里，通过评估L5对CMs中CaMKII活性和KATP通道生理的影响，研究了L5在心脏损伤中的作用。用中等浓度（即7.5μg/ mL）的L5或L1（最小负电LDL组分）处理培养的新生大鼠CM（NRCM）。检查了NRCMs的凋亡和生存力，CaMKII活性，磷酸化CaMKIIδ和NOX2 / gp91phox的表达。通过使用膜片钳技术分析了KATP的功能和动作电位（APs）。在NRCM中，L5而非L1显着诱导细胞凋亡并降低细胞活力。此外，L5降低Kir6.2表达超过50％。膜片钳分析表明，L5降低了KATP开环剂Pinacidil诱导的KATP电流（IKATP）密度。吡那地尔洗脱期间内向钾电流的部分恢复易于被IKATP阻断剂格列本脲随后抑制。L5抑制IKATP可以显着延长AP持续时间。L5还显着增加了CaMKII的活性，CaMKIIδ的磷酸化以及NOX2 / gp91phox的表达。加入CaMKII抑制剂KN93和活性氧清除剂Mn（III）TBAP可防止L5诱导的细胞凋亡。L5而非L1通过激活CaMKII途径诱导CM损伤，并通过调节AP持续时间来增加CM中的心律失常性。这些结果有助于解释L5在心血管相关疾病中的有害作用。