Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation.
Insulin resistance markedly increases cardiovascular disease risk in people with normal glucose tolerance, even after adjustment for known risk factors such as LDL, triglycerides, HDL, and systolic blood pressure. In this report, we show that increased oxidation of FFAs in aortic endothelial cells without added insulin causes increased production of superoxide by the mitochondrial electron transport chain. FFA-induced overproduction of superoxide activated a variety of proinflammatory signals previously implicated in hyperglycemia-induced vascular damage and inactivated 2 important antiatherogenic enzymes, prostacyclin synthase and eNOS. In 2 nondiabetic rodent models--insulin-resistant, obese Zucker (fa/fa) rats and high-fat diet-induced insulin-resistant mice--inactivation of prostacyclin synthase and eNOS was prevented by inhibition of FFA release from adipose tissue; by inhibition of the rate-limiting enzyme for fatty acid oxidation in mitochondria, carnitine palmitoyltransferase I; and by reduction of superoxide levels. These studies identify what we believe to be a novel mechanism contributing to the accelerated atherogenesis and increased cardiovascular disease risk occurring in people with insulin resistance.
Du
Xueliang
X
Diabetes Research Center, Albert Einstein College of Medicine, New York, New York 10461, USA.
Edelstein
Diane
D
Obici
Silvana
S
Higham
Ninon
N
Zou
Ming-Hui
MH
Brownlee
Michael
M
D000818:Animals; D001011:Aorta; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; D013481:Superoxides; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D002334:Carnitine O-Palmitoyltransferase; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D005947:Glucose