ANGIOTENSIN II INCREASES TISSUE‐SPECIFIC INHIBITOR OF METALLOPROTEINASE‐2 EXPRESSION IN RAT AORTIC SMOOTH MUSCLE CELLS IN VIVO: EVIDENCE OF A PRESSURE‐INDEPENDENT EFFECT

Abstract

1. Angiotensin (Ang) II plays a major role in vascular remodelling. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the tissue remodelling processes. The aim of the present study was to investigate whether AngII modulates TIMP-2 expression in rat aortic smooth muscle cells in vivo. 2. Angiotensin II (200 ng/kg per min, s.c.) or AngII + losartan (10 mg/kg per day, s.c.) or normal saline was administered continuously by osmotic minipumps to Sprague-Dawley rats for 1 week. In addition, the effect of endogenous AngII on TIMP-2 expression was evaluated in renovascular hypertensive rats (two kidney, one clip (2K1C) and one kidney, one clip (1K1C) models). Control rats (sham 2K1C and sham 1K1C rats) underwent sham-clipping of the left renal artery. At the end of the treatment, plasma renin activity was measured by radioimmunoassay, aortic TIMP-2 mRNA expression was evaluated by real-time polymerase chain reaction and/or northern blotting and protein expression was evaluated by immunohistochemistry. Systolic blood pressure (SBP) was measured twice a week by the tail-cuff method. 3. Exogenous AngII administration produced the expected increase in SBP (P = 0.02) compared with the control saline-treated group. The increase in SBP was abolished in AngII + losartan-treated rats. Administration of AngII caused a significant increase in TIMP-2 expression (P = 0.01) in rat aortic smooth muscle cells that was abolished in AngII + losartan-treated rats. In renovascular hypertensive rats, SBP was higher (P < 0.0001) in 2K1C and 1K1C rats compared with the corresponding sham-operated rats. Plasma renin activity was higher (P < 0.01) in 2K1C rats compared with the other groups. The expression of TIMP-2 was significantly (P < 0.05) increased only in 2K1C rats. 4. Our in vivo data demonstrate that exogenous and endogenous AngII increases TIMP-2 expression in rat aortic smooth muscle cells. This effect is not dependent on the AngII-induced increase in blood pressure and is mediated by angiotensin AT1 receptors.

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

“…128 Axel Ulrich's group discovered a pathway in 1996 for how G-protein coupled receptors such as the AT1R could phosphorylate and activate the EGFR. 129 Ang II was initially not studied, but the investigators found that ET-1, lysophosphatic acid, and thrombin all activate G-coupled receptors lacking the kinase domain by phosphorylating tyrosine residues on the EGFR and thereby activating other downstream kinases. 130 These findings were rapidly extended to Ang II.…”

“…130 These findings were rapidly extended to Ang II. 129 For example, in cardiac fibroblasts, Ang II stimulates tyrosine phosphorylation of the EGFR, a process called "transactivation." 131 Further studies reveal that stimulation of Gprotein coupled receptors leads to EGFR phosphorylation through activation of MMPs.…”

MiR‐133a regulates collagen 1A1: Potential role of miR‐133a in myocardial fibrosis in angiotensin II‐dependent hypertension

“…Col1A1 mRNA and 18S expression was evaluated using the Assay-on-Demand Gene Expression Product (Applied Biosystem), following the manufacturer's instructions, as previously described (Castoldi et al, 2007). Values are reported as Col1A1/18S mRNA ratio and expressed in arbitrary units (a.u.).…”

“…In the cardiovascular system, Angiotensin II (Ang II) promotes fibrosis by its hemodynamic and cellular effects, such as the modulation of TGFb signaling (Dzau, 2001;Schultz et al, 2002;Schroder et al, 2006;Gao et al, 2009;Leask, 2010) and the extracellular matrix turnover, through the major class of proteolitic enzymes (Campos et al, 2003;Castoldi et al, 2003Castoldi et al, , 2007Takenaka et al, 2006). Ang II has two main receptors, the Ang II type 1 receptors (AT1) and the Ang II type 2 receptors (AT2) (Timmermans et al, 1993).…”

Fabrication of an α-lipoic acid-eluting poly-(D,L-lactide-co-caprolactone) cuff for the inhibition of neointimal formation

“…Although a perivascular cuff is used in this model for the induction of restenosis, this tool may be an ideal device to evaluate the delivery and action of anti-restenotic drugs. Perivascular cuffs indirectly contact the blood or the lumen of vessels, thereby reducing the risk of thrombosis and the loss of drug by dilution resulting from blood flow (Moroi et al, 2003;Sasaki et al, 2004;Nuno et al, 2005;Castoldi et al, 2007).…”