Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice.
We hypothesized that maturation-induced vascular inflammation produces endothelial dysfunction in type II diabetes and TNFalpha plays a key role in triggering inflammation in the development of diabetes. In control (Db/db) mice aged 6, 12, 18 and 24 weeks, sodium nitroprusside (SNP) and acetylcholine (ACh) induced dose-dependent vasodilation, and dilation to ACh was blocked by the NO synthase inhibitor N (G)-monomethyl-L: -arginine. In type II diabetic (db/db) mice at age of 12, 18 and 24 weeks, ACh or flow-induced dilation was blunted compared to Db/db; endothelial function is normal at 6 weeks of age in db/db Vs. control mice, but SNP produced comparable dilation at age of 6, 12, 18 and 24 weeks. Decrements in endothelial function in db/db mice progressively increased from 6-12 to 18-24 weeks. Administration of neutralizing antibodies to TNFalpha ameliorated endothelial dysfunction in db/db mice aged 12, 18 and 24 weeks. The effect was most prominent in the younger animals. Plasma concentration, expression of TNFalpha and TNFalpha receptor 1 (TNFR1) were elevated in coronary arterioles, even at the age of 6 weeks before the development of diabetes in db/db mice compared to control mice. Superoxide production was lower in Db/db mice compared to db/db mice and increments in superoxide production in db/db mice progressively increased from 6-12 to 18-24 weeks. NAD(P)H oxidase inhibitor apocynin attenuated superoxide production in db/db mice at 12 weeks of age, mitochondria respiratory chain inhibitor rotenone attenuated superoxide production at 24 weeks in db/db and Db/db mice, but the combination of apocynin and rotenone reduced superoxide production at 18 weeks for db/db and Db/db mice. The expression of TNFalpha and its receptors increase progressively with maturation in concert with the development of diabetes. Incremental increases in TNFalpha/TNFR1 expression induces activation and production of superoxide via NAD(P)H oxidase and/or mitochondria respiratory chain, leading to endothelial dysfunction progressing to the development of type II diabetes.
Zhang
Cuihua
C
Dept. of Internal Medicine, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA. zhangcu@missouri.edu
Park
Yoonjung
Y
Picchi
Andrea
A
Potter
Barry J
BJ
D000005:Abdomen; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D001835:Body Weight; D003324:Coronary Artery Disease / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000276:immunology; D003925:Diabetic Angiopathies / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007333:Insulin Resistance / Q000276:immunology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D014657:Vasculitis / Q000150:complications / Q000276:immunology* / Q000378:metabolism
D001786:Blood Glucose; D008055:Lipids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha