β-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway
β-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway
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DOI：
10.1161/01.res.0000054624.03539.b4
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发表时间：
2003-02-07
影响因子：
20.1
通讯作者：
Colucci, WS
中科院分区：
文献类型：
--
作者：
Remondino, A;Kwon, SH;Colucci, WS
β-肾上腺素能受体 (betaAR) 的刺激会导致成年大鼠心室肌细胞 (ARVM) 凋亡。活性氧 (ROS) 在介导 betaAR 刺激的细胞凋亡中的作用尚不清楚。在哌唑嗪 (100 nmol/L) 存在下，用去甲肾上腺素 (10 μmol/L) 刺激 betaAR 24 小时，根据 TUNEL 染色测定，凋亡肌细胞的数量增加了 3.6 倍。超氧化物歧化酶/过氧化氢酶模拟物 Mn(III) 四（1-甲基-4-吡啶基）五氯化卟啉（MnTMPyP；10 μmol/L）和 Euk-134 分别使 betaAR 刺激的细胞凋亡减少 89+/-6% 和 76+/-10%。感染表达过氧化氢酶的腺病毒可使βAR刺激的细胞凋亡减少82+/-15%。线粒体通透性转换孔抑制剂bongkrekicacid(50μmol/L)使βAR刺激的细胞凋亡减少76+/-8%，半胱天冬酶抑制剂zVAD-fmk(25μmol/L)使βAR刺激的细胞凋亡减少62+/-11%。 betaAR 刺激的细胞色素 c 释放被 MnTMPyP 抑制。 betaAR 刺激引起 c-Jun NH2 末端激酶 (JNK) 激活，该激活被 MnTMPyP 消除。用表达显性失活 JNK 的腺病毒转染可抑制 βAR 刺激的细胞凋亡 81+/-12%，而 JNK 抑制剂 SP600125 抑制 βAR 刺激的细胞凋亡和细胞色素 c 释放。因此，ARVM 中 betaAR 刺激的细胞凋亡涉及线粒体死亡途径的 ROS/JNK 依赖性激活。
Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 mumol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6-fold. The superoxide dismutase/catalase mimetics Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; 10 mumol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 mumol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 mumol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.