Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice
- 3 July 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Basic Research in Cardiology
- Vol. 103 (5), 407-416
- https://doi.org/10.1007/s00395-008-0725-0
Abstract
We hypothesized that maturation-induced vascular inflammation produces endothelial dysfunction in type II diabetes and TNFα 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 TNFα 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 TNFα and TNFα 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 TNFα and its receptors increase progressively with maturation in concert with the development of diabetes. Incremental increases in TNFα/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.This publication has 26 references indexed in Scilit:
- Release of TNF-α during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosisAmerican Journal of Physiology-Heart and Circulatory Physiology, 2007
- TNF- Contributes to Endothelial Dysfunction in Ischemia/Reperfusion InjuryArteriosclerosis, Thrombosis, and Vascular Biology, 2006
- Activation of JNK and xanthine oxidase by TNF-α impairs nitric oxide-mediated dilation of coronary arteriolesJournal of Molecular and Cellular Cardiology, 2006
- Reduced release of nitric oxide to shear stress in mesenteric arteries of aged ratsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2004
- Myocardial Dysfunction With Coronary MicroembolizationCirculation Research, 2002
- Mechanisms of Increased Vascular Superoxide Production in Human Diabetes MellitusCirculation, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- TUMOR NECROSIS FACTOR RECEPTOR AND Fas SIGNALING MECHANISMSAnnual Review of Immunology, 1999
- C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, and Endothelial DysfunctionArteriosclerosis, Thrombosis, and Vascular Biology, 1999
- Thymic lymphomas mediate non-MHC-restricted, TNF-dependent lysis of the murine sarcoma WEHI-164Cellular Immunology, 1991