Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro
Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro
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DOI：
10.1161/01.res.85.2.147
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发表时间：
1999-07-23
影响因子：
20.1
通讯作者：
Colucci, WS
中科院分区：
文献类型：
--
作者：
Siwik, DA;Tzortzis, JD;Colucci, WS
氧化应激与心肌衰竭的病理生理学有关。我们验证了内源性抗氧化酶抑制可以调节心肌细胞表型的假设。用二乙基二硫代氨基甲酸（DDC）处理离体乳鼠心室肌细胞，DDC是一种胞浆（Cu，Zn）和胞外超氧化物歧化酶（SOD）的抑制剂。DDC浓度依赖性地抑制SOD活性，增加细胞内超氧阴离子自由基。低浓度（1 μ mol/L）DDC刺激心肌细胞生长，表现为蛋白质合成、细胞蛋白、前心钠素原和c-fos mRNA的增加以及肌浆网Ca 2 + ATP酶mRNA的降低。这些行动都抑制超氧化物清除剂Tiron（4，5-二羟基-1，3-苯二磺酸）。较高浓度的DDC（100 μ mol/L）刺激心肌细胞凋亡，证明了DNA梯状，核形态特征，原位末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL），并增加酒吧mRNA的表达。DDC刺激的细胞凋亡被SOD/过氧化氢酶模拟物EUK-8抑制。DDC的生长和凋亡作用通过用黄嘌呤加黄嘌呤氧化酶产生超氧化物来模拟。因此，由SOD抑制引起的细胞内超氧化物的增加导致心肌细胞中生长程序的激活和凋亡。这些发现支持氧化应激在心肌重塑和衰竭的发病机制中的作用。
Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that inhibition of endogenous antioxidant enzymes can regulate the phenotype of cardiac myocytes. Neonatal rat ventricular myocytes in vitro were exposed to diethyldithiocarbamic acid (DDC), an inhibitor of cytosolic (Cu, Zn) and extracellular superoxide dismutase (SOD). DDC inhibited SOD activity and increased intracellular superoxide in a concentration-dependent manner. A low concentration (1 mu mol/L) of DDC stimulated myocyte growth, as demonstrated by increases in protein synthesis, cellular protein, prepro-atrial natriuretic peptide, and c-fos mRNAs and decreased sarcoplasmic reticulum Ca2+ ATPase mRNA. These actions were all inhibited by the superoxide scavenger Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid). Higher concentrations of DDC (100 mu mol/L) stimulated myocyte apoptosis, as evidenced by DNA laddering, characteristic nuclear morphology, in situ terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL), and increased bar mRNA expression. DDC-stimulated apoptosis was inhibited by the SOD/catalase mimetic EUK-8. The growth and apoptotic effects of DDC were mimicked by superoxide generation with xanthine plus xanthine oxidase. Thus, increased intracellular superoxide resulting from inhibition of SOD causes activation of a growth program and apoptosis in cardiac myocytes. These findings support a role for oxidative stress in the pathogenesis of myocardial remodeling and failure.