Angiotensin Ii Increases Tissue Inhibitor of Matrix Metalloproteinase-1 (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 Angiotensin II (Ang II) plays a fundamental role in vascular remodeling. Aim of the study was to investigate whether Ang II modulates TIMP-1 expression in rat aortic smooth muscle cells. In vitro, Ang II induces TIMP-1 mRNA expression in 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 AT1 receptors, since it was blocked by losartan. The increase in TIMP-1 expression was present after the first Ang II treatment, while 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/min. s.c.) either for 6 or for 25 days. Control rats received physiological saline. After the treatment, systolic blood pressure was significantly higher (p<0.01), while plasma renin activity was suppressed (p<0.01), in Ang II-treated rats. Ang II increased TIMP-1 expression in aorta of Ang II treated rats both at mRNA (p<0.05) and protein level as evaluated by Western blotting (p<0.05) and/or immunohistochemistry. Neither histological modifications at vascular wall, nor differences in collagen content in the tunica media were present in both Ang II-treated groups as compared to 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 rat aorta. TIMP-1 induction by Ang II in aortic smooth muscle cells occurs in absence of histological changes at the vascular wall.