Ishizawa Makoto, Mizushige Katsufumi, Noma Takahisa, Namba Tsunetatsu, Guo Peng, Murakami Kazushi, Tsuji Teppei, Miyatake Akira, Ohmori Koji, Kohno Masakazu
Second Department of Internal Medicine, Kagawa University School of Medicine, Miki, Kita, Kagawa, 761-0793, Japan.
Life Sci. 2006 May 15;78(25):2974-82. doi: 10.1016/j.lfs.2006.02.029. Epub 2006 Mar 31.
Excessive beta-adrenergic stimulation causes cardiac toxicity, which also contributes to cardiac oxidative stress. Although uncoupling protein 2 (UCP2), a member of the mitochondrial inner membrane carrier family, can regulate energy efficiency and oxidative stress in mitochondria, little data exist regarding interactions between UCP2 expression and beta-adrenergic stimulation induced cardiac oxidative damage. We investigated whether chronic beta-adrenergic stimulation induces myocardial energy metabolism abnormality via oxidative stress, including any role of UCP2. We also examined whether 3-methyl-1-phenyl-2-pyrazolin-5-one (MIC-186; edaravone), a potent free radical scavenger, has cardioprotective effects against beta-adrenergic stimulation. Male Sprague-Dawley rats received isoproterenol (1.2 mg/kg/day) subcutaneously or/and edaravone (30 mg/kg/day) orally. Isoproterenol increased the heart/body weight ratio, accompanied by an increase in the level of myocardial thiobarbituric acid reactive substances (TBARS) and a decreased phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio. Isoproterenol also markedly increased expressions of UCP2 mRNA (1.74 fold vs. non-isoproterenol) and protein (1.93 fold vs. non-isoproterenol). Edaravone had no apparent effect in hypertrophic responses, but significantly prevented both increases in TBARS and decreases in the PCr/ATP ratio. Edaravone also prevented increases in UCP2 mRNA (0.76 fold vs. isoproterenol) and protein (0.62 fold vs. isoproterenol) expressions against isoproterenol administration. Our results suggest that chronic beta-adrenergic stimulation induces myocardial energy inefficiency via excessive oxidative stress. The antioxidant effect of edaravone has potential to improve energy metabolism abnormalities against beta-adrenergic stimulation. Adequate regulation of UCP2 expression through artificial reduction of oxidative stress may play an important role in protection of the myocardial energy metabolism.
过度的β-肾上腺素能刺激会导致心脏毒性，这也会导致心脏氧化应激。尽管解偶联蛋白2（UCP2）是线粒体内膜载体家族的一员，可调节线粒体中的能量效率和氧化应激，但关于UCP2表达与β-肾上腺素能刺激诱导的心脏氧化损伤之间的相互作用的数据很少。我们研究了慢性β-肾上腺素能刺激是否通过氧化应激诱导心肌能量代谢异常，包括UCP2的任何作用。我们还研究了强效自由基清除剂3-甲基-1-苯基-2-吡唑啉-5-酮（MIC-186；依达拉奉）对β-肾上腺素能刺激是否具有心脏保护作用。雄性Sprague-Dawley大鼠皮下注射异丙肾上腺素（1.2 mg/kg/天）或/和口服依达拉奉（30 mg/kg/天）。异丙肾上腺素增加了心脏/体重比，同时心肌硫代巴比妥酸反应性物质（TBARS）水平升高，磷酸肌酸（PCr）与三磷酸腺苷（ATP）的比值降低。异丙肾上腺素还显著增加了UCP2 mRNA（与非异丙肾上腺素组相比增加1.74倍）和蛋白质（与非异丙肾上腺素组相比增加1.93倍）的表达。依达拉奉对肥厚反应没有明显影响，但显著预防了TBARS的增加和PCr/ATP比值的降低。依达拉奉还预防了异丙肾上腺素给药后UCP2 mRNA（与异丙肾上腺素组相比为0.76倍）和蛋白质（与异丙肾上腺素组相比为0.62倍）表达的增加。我们的结果表明，慢性β-肾上腺素能刺激通过过度氧化应激诱导心肌能量低效。依达拉奉的抗氧化作用有可能改善β-肾上腺素能刺激引起的能量代谢异常。通过人为降低氧化应激来充分调节UCP2表达可能在保护心肌能量代谢中起重要作用。
