Endothelin-mediated remodeling in aortas of diabetic rats

• Published in: Diabetes/metabolism research and reviews 2005-07, Vol.21 (4), p.367-375
• Main Authors: Fukuda, Gen, Khan, Zia A., Barbin, Yousef P., Farhangkhoee, Hana, Tilton, Ronald G., Chakrabarti, Subrata
• Format: Article
• Language: English
• Subjects: Animals; Aorta - drug effects; Aorta - pathology; Aorta - physiopathology; Biological and medical sciences; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; DNA Primers; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelin-1 - metabolism; endothelins; Endothelins - antagonists & inhibitors; Endothelins - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; extracellular matrix; Fibronectins - genetics; Fibronectins - metabolism; Isoxazoles - pharmacology; macroangiopathy; Male; Medical sciences; oncofetal fibronectin; Plasminogen Activator Inhibitor 1 - genetics; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA - genetics; RNA - isolation & purification; SMemb; Sulfonamides - pharmacology; Tunica Intima - drug effects; Tunica Intima - pathology; Tunica Media - drug effects; Tunica Media - pathology
• ISSN: 1520-7552; 1520-7560
• DOI: 10.1002/dmrr.527

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.