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Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice

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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.

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Acknowledgments

Funding sources: This study was supported by grants from Pfizer Atorvastatin Research Award (2004-37), American Heart Association Scientist Development Grant (110350047A) and NIH grants (RO1-HL077566 and RO1-HL085119) to Dr. Cuihua Zhang. Conflicts of interest None.

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Authors and Affiliations

  1. Dept. of Internal Medicine, Dalton Cardiovascular Research Center, University of Missouri-Columbia, 134 Research Park Drive, Columbia, MO, 65211, USA

    Cuihua Zhang MD, PhD

  2. Dept. of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, MO, USA

    Cuihua Zhang MD, PhD

  3. Dept. of Nutritional Sciences, University of Missouri-Columbia, Columbia, MO, USA

    Cuihua Zhang MD, PhD

  4. Michael E DeBakey Institute, Texas A&M University, College Station, TX, USA

    Cuihua Zhang MD, PhD, Yoonjung Park & Andrea Picchi

  5. Dept. of Physiology, LSU Health Sciences Center, New Orleans, LA, USA

    Barry J. Potter

Authors
  1. Cuihua Zhang MD, PhD
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  2. Yoonjung Park
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  3. Andrea Picchi
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  4. Barry J. Potter
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Corresponding author

Correspondence to Cuihua Zhang MD, PhD.

Additional information

Returned for 1. Revision: 12 November 2007 1. Revision received: 23 November 2007

Returned for 2. Revision: 19 December 2007 2. Revision received: 23 December 2007

Returned for 3. Revision: 4 January 2008 3. Revision received: 24 March 2008

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Zhang, C., Park, Y., Picchi, A. et al. Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice. Basic Res Cardiol 103, 407–416 (2008). https://doi.org/10.1007/s00395-008-0725-0

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  • DOI: https://doi.org/10.1007/s00395-008-0725-0

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