Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice

We hypothesized that maturation-induced vascular inflammation produces endothelial dysfunction in type 11 diabetes and TNF alpha 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 11 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 TNF alpha 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 TNF alpha and TNF alpha receptor I (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/clb 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 TNF alpha and its receptors increase progressively with maturation in concert with the development of diabetes. Incremental increases in TNF alpha/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.