ANG II increases TIMP-1 expression in rat aortic smooth muscle cells in vivo.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tissue remodeling processes. TIMP-1 is the main native inhibitor of MMPs and it contributes to the development of tissue fibrosis. It is known that ANG II plays a fundamental role in vascular remodeling. In this study, we investigated whether ANG II modulates TIMP-1 expression in rat aortic smooth muscle cells. In vitro, ANG II induces TIMP-1 mRNA expression in a dose-dependent manner. The maximal increase in TIMP-1 expression was present after 3 h of ANG II stimulation. The ANG II increase in TIMP-1 expression was mediated by the ANG type 1 receptors because it was blocked by losartan. The increase in TIMP-1 expression was present after the first ANG II treatment, whereas repeated treatments (3 and 5 times) did not modify TIMP-1 expression. In vivo, exogenous ANG II was administered to Sprague-Dawley rats (200 ng. kg(-1). min(-1) sc) for 6 and 25 days. Control rats received physiological saline. After treatment, systolic blood pressure was significantly higher (P < 0.01), whereas plasma renin activity was suppressed (P < 0.01), in ANG II-treated rats. ANG II increased TIMP-1 expression in the aorta of ANG II-treated rats both at the mRNA (P < 0.05) and protein levels as evaluated by Western blotting (P < 0.05) and/or immunohistochemistry. Neither histological modifications at the vascular wall nor differences in collagen content in the tunica media were present in both the ANG II- and saline-treated groups. Our data demonstrate that ANG II increases TIMP-1 expression in rat aortic smooth muscle cells. In vivo, both short- and long-term chronic ANG II treatments increase TIMP-1 expression in the rat aorta. TIMP-1 induction by ANG II in aortic smooth muscle cells occurs in the absence of histological changes at the vascular wall.
Castoldi
Giovanna
G
Unitá Didattico Assistenziale Nefrocardiovascolare, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Università degli Studi di Milano-Bicocca 20052, Monza, Italy.
Di Gioia
Cira R T
CR
Pieruzzi
Federico
F
D'Orlando
Cristina
C
Van De Greef
Willy M M
WM
Busca
Giuseppe
G
Sperti
Giovanni
G
Stella
Andrea
A
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007260:Infusion Pumps; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D000804:Angiotensin II