An antioxidant treatment potentially protects myocardial energy metabolism by regulating uncoupling protein 2 expression in a chronic beta-adrenergic stimulation rat model.
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.
Second Department of Internal Medicine, Kagawa University School of Medicine, Miki, Kita, Kagawa, 761-0793, Japan. mkto@med.kagawa-u.ac.jp
Makoto
M
Ishizawa
Katsufumi
K
Mizushige
Takahisa
T
Noma
Tsunetatsu
T
Namba
Peng
P
Guo
Kazushi
K
Murakami
Teppei
T
Tsuji
Akira
A
Miyatake
Koji
K
Ohmori
Masakazu
M
Kohno
D000318:Adrenergic beta-Agonists / Q000009:adverse effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077553:Edaravone; D004734:Energy Metabolism / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007473:Ion Channels; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071246:Uncoupling Protein 2
D000318:Adrenergic beta-Agonists; D000975:Antioxidants; D002316:Cardiotonic Agents; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000077553:Edaravone; D000983:Antipyrine