Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats.
Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.80 +/- 0.05 vs. -7.11 +/- 0.05 log(10) mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED(50), -7.16 +/- 0.03 and -7.14 +/- 0.05 log(10) mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.
Chinen
Ichiro
I
Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.
Shimabukuro
Michio
M
Yamakawa
Ken
K
Higa
Namio
N
Matsuzaki
Toshihiro
T
Noguchi
Katsuhiko
K
Ueda
Shinichiro
S
Sakanashi
Matao
M
Takasu
Nobuyuki
N
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D050171:Dyslipidemias / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D014661:Vasoconstriction / Q000187:drug effects
D000098:Acetophenones; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D011804:Quinolines; D017382:Reactive Oxygen Species; C056165:acetovanillone; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C108475:pitavastatin