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Am J Physiol Endocrinol Metab 294: E978-E986, 2008. First published March 18, 2008; doi:10.1152/ajpendo.00003.2008
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Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis

Elena Galluccio,1 PierMarco Piatti,1,2 Lorena Citterio,1 Pietro C. G. Lucotti,1 Emanuela Setola,1 Laura Cassina,1 Matteo Oldani,1 Ivana Zavaroni,3 Emanuele Bosi,1,2 Antonio Colombo,1 Ottavio Alfieri,1,2 Giorgio Casari,1,2 Gerald M. Reaven,4 and Lucilla D. Monti1

1Scientific Institute San Raffaele, Milan; 2Vita-Salute University Scientific Institute San Raffaele, Milan; 3Università di Parma, Parma, Italy; and 4Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California

Submitted 2 January 2008 ; accepted in final form 15 March 2008

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.

NOS3 gene variants; coronary artery disease; type 2 diabetes


Address for reprint requests and other correspondence: L. D. Monti, Diabetes Core Lab, Medicine Division, Diabetology and Endocrinology and Metabolic Disease Unit, Scientific Institute San Raffaele, Via Olgettina 60, 20132 Milan, Italy (e-mail: monti.lucilla{at}hsr.it)






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