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.
Ishizawa
Makoto
M
Second Department of Internal Medicine, Kagawa University School of Medicine, Miki, Kita, Kagawa, 761-0793, Japan. mkto@med.kagawa-u.ac.jp
Mizushige
Katsufumi
K
Noma
Takahisa
T
Namba
Tsunetatsu
T
Guo
Peng
P
Murakami
Kazushi
K
Tsuji
Teppei
T
Miyatake
Akira
A
Ohmori
Koji
K
Kohno
Masakazu
M
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