Ca 2+ Influx–Induced Sarcoplasmic Reticulum Ca 2+ Overload Causes Mitochondrial-Dependent Apoptosis in Ventricular Myocytes

心肌细胞 内质网 细胞凋亡 DNA梯 生物 分子生物学 内科学 内分泌学 化学 细胞生物学 程序性细胞死亡 生物化学 医学 DNA断裂
作者
Xiongwen Chen,Xiaoying Zhang,Hajime Kubo,David M. Harris,Geoffrey Mills,Jed Moyer,Remus M. Berretta,Sabine Telemaque Potts,James D. Marsh,Steven R. Houser
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:97 (10): 1009-1017 被引量:194
标识
DOI:10.1161/01.res.0000189270.72915.d1
摘要

Increases in Ca 2+ influx through the L-type Ca 2+ channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca 2+ loading and the amplitude of the cytosolic Ca 2+ transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca 2+ influx through the LTCC cause apoptosis if the excessive influx results in SR Ca 2+ overload. Feline ventricular myocytes (VMs) in primary culture were infected with either an adenovirus (Ad) containing a rat Cav1.2 β 2a subunit-green fluorescent protein (GFP) fusion gene (Adβ 2a ) to increase Ca 2+ influx or with AdGFP as a control. Significantly fewer β 2a -VMs (21.4±5.6%) than GFP-VMs (99.6±1.7%) were viable at 96 hours. A fraction of β 2a -VMs (20.8±1.8%) contracted spontaneously (SC-β 2a -VMs), and viability was significantly correlated with the percentage of SC-β 2a -VMs. Higher percentages of apoptotic nuclei, DNA laddering, and cytochrome C release were detected in β 2a -VMs. This apoptosis was prevented with pancaspase or caspase-3 or caspase-9 inhibitors. L-type calcium current (I Ca-L ) density was greater in β 2a -VMs (23.4±2.8 pA/pF) than in GFP-VMs (7.6±1.6 pA/pF). SC-β 2a -VMs had higher diastolic intracellular Ca 2+ (Indo-1 ratio: 1.1±0.1 versus 0.7±0.03, P <0.05) and systolic Ca 2+ transients (1.89±0.27 versus 0.80±0.08) than GFP-VMs. Inhibitors of Ca 2+ influx, SR Ca 2+ uptake and release, mitochondrial Ca 2+ uptake, mitochondrial permeation transition pore, calpain, and Bcl-2-associated X protein protected β 2a -VMs from apoptosis. These results show that persistent increases in Ca 2+ influx through the I Ca-L enhance contractility but lead to apoptosis through a mitochondrial death pathway if SR Ca 2+ overload is induced.

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