Compromised Arterial Function in Human Type 2 Diabetic Patients

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 8; pp. 2415 - 2423
• Main Authors: Okon, Elena B, Chung, Ada W Y, Rauniyar, Pooja, Padilla, Eugenia, Tejerina, Teresa, McManus, Bruce M, Luo, Honglin, van Breemen, Cornelis
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2005
• Subjects: Adult; Aged; Arteries - drug effects; Arteries - physiopathology; Atherosclerosis; Blood vessels; Coronary vessels; Diabetes; Diabetes Mellitus, Type 2 - physiopathology; Endothelium; Endothelium, Vascular - physiopathology; Female; Humans; Hypertension; Insulin; Investigations; Kinases; Male; Mammary Arteries - enzymology; Mammary Arteries - physiopathology; Microcirculation disorders; Middle Aged; Muscle, Smooth, Vascular - physiopathology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroprusside - pharmacology; Phenylephrine - pharmacology; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Risk factors; Signal Transduction; Smooth muscle; Type 2 diabetes; Vasoconstriction; Veins & arteries
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.8.2415

Compromised Arterial Function in Human Type 2 Diabetic Patients Elena B. Okon 1 , Ada W.Y. Chung 1 , Pooja Rauniyar 1 , Eugenia Padilla 2 , Teresa Tejerina 2 , Bruce M. McManus 1 , Honglin Luo 1 and Cornelis van Breemen 1 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 Address correspondence and reprint requests to Elena B. Okon, PhD, iCAPTURE Center, St. Paul’s Hospital, Room 166, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6. E-mail: eokon{at}mrl.ubc.ca Abstract 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 (Thr 308 and Ser 473 ) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr 308 ) 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 ω-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. eNOS, endothelial nitric oxide synthase IMA, internal mammary artery iNOS, inducible nitric oxide synthase l-NAME, Nω-nitro-l-arginine methyl ester PI3K, phosphatidylinositol 3-kinase SNP, sodium nitroprusside Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 2, 2005. Received September 21, 2004. DIABETES