过刊浏览

L-型钙通道自身调控异常参与缺血再灌注心肌钙超载的形成

岳志杰¹, 石展², 胡波², 王振国², 杜昱蕾^1,*

¹白求恩医务士官学校内科教研室，石家庄 050081；²中国人民解放军第260医院，石家庄 050047

摘要

钙超载作为心肌缺血再灌注损伤的重要机制之一，其形成原因与治疗策略一直是研究的热点。心肌遭受缺血再灌注后，参与细胞内钙循环的L-型电压依赖钙通道(L-type voltage-dependent calcium channel, L-VDCC)、肌浆网钙ATP酶2a (sarco/endoplasmic reticulum ATPase 2a, SERCA2a)和受磷蛋白(phospholamban, PLB)、Ryanodine受体2 (RyR2)、Na⁺/Ca²⁺交换体、Na⁺/H⁺交换体等多种蛋白功能异常，导致舒张期[Ca²⁺]_i上升，钙瞬变幅度降低，细胞出现钙超载。[Ca²⁺]_i升高的过程大致可分为两个阶段：早期的[Ca²⁺]_i升高过程(部分由钙通道介导)和晚期的[Ca²⁺]_i升高过程(主要由Na⁺/Ca²⁺交换体介导)。L-VDCC活性增加参与钙超载的形成，但是L-VDCC蛋白在缺血再灌注过程中的分子变化机制尚不清楚。L-VDCC通道调控方式包括两类：自身调节和外源性调节，其中外源性调节蛋白PKG和PKA的调控不能解释细胞水平的L-VDCC活性增加现象，而在缺血再灌注过程中，钙依赖的失活(calcium-dependent inactivation, CDI)效应减弱、钙依赖的易化(calcium-dependent facilitation, CDF)效应增强、羧基远端部分肽链(distal carboxy terminus, DCT)的抑制效应减弱，这三种自身调节机制的改变引起L-VDCC活性的增加。因此，可以认为L-VDCC通道自身调控异常参与缺血再灌注损伤中心肌细胞钙超载的形成。

关键词： 心脏; 缺血再灌注损伤 ; 钙超载 ; L-型电压依赖钙通道

分类号：R331.3

L-VDCC autoregulation abnormality contributes to calcium overload in myocardial ischemia-reperfusion injury

YUE Zhi-Jie¹, SHI Zhan², Hu Bo², WANG Zhen-Guo², DU Yu-Lei^1,*

¹Department of Internal Medicine, Norman Bethune Military Medical College, Shijiazhuang 050081, China；²The 260th Hospital of People’s Liberation Army, Shijiazhuang 050047, China

Abstract

Calcium overload is a vital mechanism of myocardial ischemia-reperfusion injury, which is a hot therapeutic target in cardiovascular research. It has been well recognized that the dysfunction of calcium relevant proteins, including L-type voltage- dependent calcium channel (L-VDCC), sarco/endoplasmic reticulum ATPase 2a (SERCA2a)/phospholamban (PLB), RyR2, Na⁺/Ca²⁺ exchanger, Na⁺/H⁺ exchanger, etc. contributes to calcium overload in cardiomyocytes during ischemia-reperfusion injury, in which the diastolic calcium concentration is increased and the amplitude of calcium transients is decreased. There are two phases in calcium increase. The early phase is partially mediated by calcium channels, and the latter one is mainly mediated by Na⁺/Ca²⁺ exchanger. L-VDCC, a main subtype of calcium channels in myocardium, is involved in calcium overload, but the underlying molecular mechanism is not well elucidated yet. L-VDCC is regulated by intrinsic and extrinsic pathways. PKG and PKA as extrinsic regulators are not proper candidates to increase L-VDCC activity of cardiomyocyte in vitro, whereas the myocardial ischemia-reperfusion injury is highly possible to enhance L-VDCC activity by delaying calcium-dependent inactivation (CDI), advancing calcium-dependent facilitation (CDF), and weakening distal carboxy terminus (DCT) inhibition. Therefore, it is rational to propose that the L-VDCC autoregulation abnormality may play an important role in calcium overload during myocardial ischemia-reperfusion injury.

Key words: Heart; ischemia-reperfusion injury ; calcium overload ; L-type voltage-dependent calcium channel

收稿日期：2017-02-26　　录用日期：2017-11-06

通讯作者：杜昱蕾　　E-mail: duyuyul@foxmail.com

DOI: 10.13294/j.aps.2017.0082

引用本文：

岳志杰, 石展, 胡波, 王振国, 杜昱蕾. L-型钙通道自身调控异常参与缺血再灌注心肌钙超载的形成[J]. 生理学报 2017; 69 (6): 861-869.

YUE Zhi-Jie, SHI Zhan, Hu Bo, WANG Zhen-Guo, DU Yu-Lei. L-VDCC autoregulation abnormality contributes to calcium overload in myocardial ischemia-reperfusion injury. Acta Physiol Sin 2017; 69 (6): 861-869 (in Chinese with English abstract).