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Submitted on August 18, 2006
Accepted on September 26, 2006
Second Department of Internal Medicine (IC, MS, NH, NT), Department of Clinical Pharmacology and Therapeutics (KY, SU), and Department of Pharmacology (TM, KN, MS), Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
* To whom correspondence should be addressed. E-mail: mshimabukuro-ur{at}umin.ac.jp or me447945@members.interq.or.jp.
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 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 ED50 value was higher in ZDF (-6.80 ± 0.05 vs. -7.111 ± 0.05 log10mol/liter, P = 0.033). Two week treatment with a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, pitavastatin (3 mg/kg/per day), or a NADPH oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED50 -7.16 ± 0.03 and -7.14 ± 0.05 log10mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator responses 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 endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.
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