Endothelin-mediated remodeling in aortas of diabetic rats

Gen Fukuda, Zia A. Khan, Yousef P. Barbin, Hana Farhangkhoee, Ronald G. Tilton, Subrata Chakrabarti

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)367-375
Number of pages9
JournalDiabetes/Metabolism Research and Reviews
Volume21
Issue number4
DOIs
StatePublished - Jul 1 2005

Keywords

  • Endothelins
  • Extracellular matrix
  • Macroangiopathy
  • Oncofetal fibronectin
  • SMemb

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Fukuda, G., Khan, Z. A., Barbin, Y. P., Farhangkhoee, H., Tilton, R. G., & Chakrabarti, S. (2005). Endothelin-mediated remodeling in aortas of diabetic rats. Diabetes/Metabolism Research and Reviews, 21(4), 367-375. https://doi.org/10.1002/dmrr.527