Research Article

Endothelin-mediated remodeling in aortas of diabetic rats

  1. Gen Fukuda1,
  2. Zia A. Khan1,
  3. Yousef P. Barbin1,
  4. Hana Farhangkhoee1,
  5. Ronald G. Tilton2,
  6. Subrata Chakrabarti1,*

Article first published online: 3 DEC 2004

DOI: 10.1002/dmrr.527

Issue

Diabetes/Metabolism Research and Reviews

Diabetes/Metabolism Research and Reviews

Volume 21, Issue 4, pages 367–375, July/August 2005

Additional Information

How to Cite

Fukuda, G., Khan, Z. A., Barbin, Y. P., Farhangkhoee, H., Tilton, R. G. and Chakrabarti, S. (2005), Endothelin-mediated remodeling in aortas of diabetic rats. Diabetes/Metabolism Research and Reviews, 21: 367–375. doi: 10.1002/dmrr.527

Author Information

  1. 1

    Department of Pathology, University of Western Ontario, London, ON, Canada

  2. 2

    Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA

*Department of Pathology, Dental Sciences Building, University of Western Ontario, London, Ontario. N6A 5C1, Canada.

Publication History

  1. Issue published online: 15 JUN 2005
  2. Article first published online: 3 DEC 2004
  3. Manuscript Accepted: 5 SEP 2004
  4. Manuscript Revised: 20 AUG 2004
  5. Manuscript Received: 7 MAY 2004

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Keywords:

  • macroangiopathy;
  • endothelins;
  • extracellular matrix;
  • oncofetal fibronectin;
  • SMemb

Abstract

Background

Smooth muscle cells proliferation and extracellular matrix (ECM) protein deposition are key features of diabetic macroangiopathy. In the present study, we have studied the role of endothelinA (ETA) receptor, the predominant receptor on smooth muscle cells, in diabetes-induced vascular hypertrophy and remodeling.

Methods

Streptozotocin-induced diabetic rats were administrated a selective ETA receptor antagonist, TBC3214, for 26 weeks. Following treatment, aortas were harvested and subjected to gene expression and morphometric analyses. We quantified fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) expression as indicators of increased ECM protein synthesis. ET-1, ET-3, transforming growth factor-β1 (TGF-β1) and angiotensinogen mRNA levels were measured to elucidate genes involved in FN expression. We have investigated an embryonic splice variant of FN, oncofetal FN, and nonmuscle myosin heavy chain (SMemb) as vascular remodeling indicators.

Results

Our results show that diabetes leads to upregulation of FN, PAI-1, ET-1, ET-3, TGF-β1 and angiotensinogen mRNA levels in association with increased medial thickness. Immunohistochemical analyses revealed concurrent protein level changes. Diabetes also upregulated oncofetal FN and SMemb mRNA levels. Treatment with TBC3214 attenuated the mRNA levels of several genes and prevented increased medial thickness.

Conclusions

These results indicate that diabetes-induced vascular hypertrophy and remodeling is associated with reexpression of embryonic forms of FN and myosin heavy chain. Such changes are ET-dependent and may be mediated via TGF-β1 and angiotensin. Copyright © 2004 John Wiley & Sons, Ltd.

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