Role of cyclooxygenase 2 in insulin resistance mediated vascular endothelial dysfunction in type 2 diabetic db/db mice

Abstract

Objective To explore the mechanism of insulin resistance on endothelial dysfunction in type 2 diabetic mellitus(T2DM) mice. Methods Mesenteric arteries isolated from T2DM mice (db/db) and normal control group (db/+)(n=10 for each group) were subjected to wire-myograph for measurement of vasoreactivity response to insulin treatment. The expression levels of cyclooxygenase and putative constrictor prostanoids in the arteries were determined using quantitative polymerase chain reaction(QT-PCR) analysis and enzyme linked immunosorbent assay(ELISA), respectively. The t-test and one way analysis of variance were used for statistical analysis. Results Insulin evoked endothelium-dependent vasoconstriction in mesenteric arteries from db/db mice in a dose dependent manner, max vasoconstriction was 28.2%±4.1% to precontraction. Both MEK inhibitor and cyclooxygenase-2 (COX-2) specific inhibitor could reverse the insulin-stimulated vasoconstriction, max vasorelaxation was 41.2%±2.2% and 26.3%±3.2%, respectively(t= 47.3,33.2,P<0.05). The level of COX-2 in the db/db mice was 4 folds of that in the db/+ mice. COX-2-mediated prostaglandin F2a (PGF2a) increased. After COX-2 inhibitor NS-398 pro-treatment, the protein expression of PGF2a decreased from (1 614±8) to (536±4) ng/g(t=381.9, P<0.05)while the level of PGF1a was not decreased. Conclusions Insulin may induce endothelium-dependent vasoconstriction in db/db mice. Increased expression and activity of COX-2 maybe involve in insulin resistance on vascular endothelial function. Key words: Diabetes mellitus, type 2; Endothelium; Cyclooxygenase 2; Insulin resistance