Endothelin-mediated remodeling in aortas of diabetic rats.
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 endothelin(A) (ET(A)) receptor, the predominant receptor on smooth muscle cells, in diabetes-induced vascular hypertrophy and remodeling.


METHODS
Streptozotocin-induced diabetic rats were administrated a selective ET(A) 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-beta1 (TGF-beta1) 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-beta1 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-beta1 and angiotensin.
Fukuda
Gen
G
Department of Pathology, University of Western Ontario, London, ON, Canada.
Khan
Zia A
ZA
Barbin
Yousef P
YP
Farhangkhoee
Hana
H
Tilton
Ronald G
RG
Chakrabarti
Subrata
S
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D017931:DNA Primers; D019332:Endothelin-1; D016232:Endothelins; D005353:Fibronectins; D007555:Isoxazoles; D017395:Plasminogen Activator Inhibitor 1; D013449:Sulfonamides; C424912:TBC 3214; D012313:RNA