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Vascular Lipotoxicity: Endothelial Dysfunction via Fatty-Acid-Induced Reactive Oxygen Species Overproduction in Obese Zucker Diabetic Fatty Rats

Second Department of Internal Medicine (I.C., M.Sh., N.H., N.T.), Department of Clinical Pharmacology and Therapeutics (K.Y., S.U.), and Department of Pharmacology (T.M., K.N., M.Sa.), Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan

Address all correspondence and requests for reprints to: Michio Shimabukuro, M.D., Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail: mshimabukuro-ur{at}umin.ac.jp or me447945{at}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 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 ED₅₀ value was higher in ZDF (–6.80 ± 0.05 vs. –7.11 ± 0.05 log₁₀ 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 (ED₅₀, –7.16 ± 0.03 and –7.14 ± 0.05 log₁₀ 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.

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