Statin reverses reduction of adiponectin receptor expression in infarcted heart and in TNF-alpha-treated cardiomyocytes in association with improved glucose uptake.
Statin treatment improves insulin resistance in skeletal muscle. Thus this study assessed whether statin may affect the myocardial expression levels of AdipoR1 and AdipoR2, receptors of adiponectin that enhance insulin sensitivity, and whether statin may improve insulin resistance in cardiomyocytes. Myocardial infarction (MI) was created by the ligation of the left coronary artery in male mice. Expression levels of mRNA and protein levels of AdipoR1 but not of AdipoR2 were significantly decreased in the remote area as well as in the healed infarcted area in the left ventricles 4 wk after MI. Oral administration of pravastatin (50 mg.kg(-1).day(-1) for 4 wk after MI) reversed the decrease in myocardial expression levels of AdipoR1 independently of changes in serum lipid profiles and insulin levels. With the use of cultured cardiomyocytes, incubation with tumor necrosis factor (TNF)-alpha, a mediator of postinfarction myocardial dysfunction, inhibited AdipoR1 mRNA and protein expression levels. Coincubation of the cells with pravastatin reversed the inhibitory effects of TNF-alpha on AdipoR1 expression. In parallel, pravastatin reversed the TNF-alpha-induced decrease in globular adiponectin-induced 2-deoxy-d-[(3)H]glucose uptake in insulin-treated cultured cells. Moreover, this effect of pravastatin was inhibited by the suppression of AdipoR1 expression by small-interfering RNA specific for AdipoR1. Incubation with H(2)O(2) reduced AdipoR1 expression in cultured cardiomyocytes that were attenuated by N-acetyl-l-cysteine or pravastatin. Pravastatin suppressed TNF-alpha-induced intracellular oxidants in cultured cardiomyocytes. In conclusion, pravastatin reversed the reduction of AdipoR1 expression in postinfarction mouse myocardium and in TNF-alpha-treated cardiomyocytes partly through an antioxidative mechanism in association with improved glucose uptake.
Saito
Yukio
Y
Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo City, Yamanashi 409-3898, Japan.
Fujioka
Daisuke
D
Kawabata
Ken-ichi
K
Kobayashi
Tsuyoshi
T
Yano
Toshiaki
T
Nakamura
Takamitsu
T
Kodama
Yasushi
Y
Takano
Hajime
H
Kitta
Yoshinobu
Y
Obata
Jyun-ei
JE
Kugiyama
Kiyotaka
K
D000111:Acetylcysteine / Q000494:pharmacology; D052242:Adiponectin / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008026:Ligation; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D052242:Adiponectin; D000975:Antioxidants; D001786:Blood Glucose; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D008055:Lipids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C475419:adiponectin receptor 1, mouse; C504339:adiponectin receptor 1, rat; C475421:adiponectin receptor 2, mouse; D006861:Hydrogen Peroxide; D005947:Glucose; D017035:Pravastatin; D000111:Acetylcysteine