LAUSR

Objective: Angiotensin II (Ang II) has been linked to vascular senescence; however, the molecular mechanism(s) by which this occurs remain unknown. We hypothesized that Ang II induced vascular smooth muscle cell (SMC) senescence by regulating the expression of cysteine-rich angiogenic protein 61 (CYR61). Also, we evaluated the role of Ang II type 1 receptor blocker (ARB), fimasartan in vascular senescence. Design and method: We treated human coronary artery smooth muscle cells (hCSMCs) with Ang II and measured senescent cells by senescence associated &bgr;-galactosidase (SA-&bgr;-Gal). To evaluate the effect of CYR61 on calcification, VSMCs were transfected with adenoviral vectors expressing CYR61 (Ad-CYR61) at 100 multiplicities of infection (mois). As a control, an adenoviral vector expressing only green fluorescent protein (Ad-GFP) was used. Results: SA-&bgr;-Gal (+) cells were increased in Ang II group (18.75 ± 1.75%) compared with the control (11.7 ± 2.75%), which was significantly attenuated by fimasartan administration (6.5 ± 1.0%). Molecular markers related with cellular senescence, p53 and p16 expressions, were both significantly increased by angiotensin II (p53: 1.39 ± 0.10, p16: 1.19 ± 0.06 fold vs control, both p < 0.05), which were completely suppressed by fimasartan (p53: 1.02 ± 0.07, p16: 0.97 ± 0.07 fold vs control, both p = 0.002). In addition, it was confirmed that CYR61 was induced by AngII. As CYR61 was independently increased, the number of SA-&bgr;-Gal positive cells was increased (33.0 ± 3.1% vs 9.5 ± 1.3% in control), and as CYR61 was inhibited, the number was decreased (11.0 ± 0.5% vs 24.7 ± 0.9% in AngII). Also, Fimasartan inhibited the activation of ERK and p38 MAPK by Angiotensin II. As ERK was inhibited, CYR61 and p53 decreased, And as p38 MAPK was inhibited, CYR61, p53 and p16 decreased. Conclusions: In conclusion, fimasartan provides anti-senescence effect by suppressing CYR61 and ERK/p38 MAPK/p53 signaling pathway in hCSMCs. In addition, this anti-senescence effect will be a basis for identification of pleiotropic effect by ARBs.