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Compromised Arterial Function in Human Type 2 Diabetic Patients

¹ James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia and St. Paul’s Hospital, Vancouver, British Columbia, Canada
² Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain

Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr³⁰⁸ and Ser⁴⁷³) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr³⁰⁸) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of N-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms.

Abbreviations: eNOS, endothelial nitric oxide synthase; IMA, internal mammary artery; iNOS, inducible nitric oxide synthase; L-NAME, N-nitro-L-arginine methyl ester; PI3K, phosphatidylinositol 3-kinase; SNP, sodium nitroprusside

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