Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse.
Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.
Ding
Hong
H
School of Medical Sciences, RMIT University, Bundoora West Campus, Bundoora, Victoria 3083, Australia. hong.ding@rmit.edu.au
Hashem
Michael
M
Wiehler
William B
WB
Lau
Winnie
W
Martin
Jacqueline
J
Reid
Julianne
J
Triggle
Chris
C
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D001685:Biological Factors / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000097006:Gap Junction alpha-4 Protein
D000109:Acetylcholine; D001057:Apolipoproteins E; D001685:Biological Factors; D017630:Connexins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013311:Streptozocin; D014665:Vasodilator Agents; D000097006:Gap Junction alpha-4 Protein; C496900:Kcnn3 protein, mouse; C067410:endothelium-dependent hyperpolarization factor; C496315:Nos3 protein, mouse