The Role Of VPO1in Hypertensive Rat Vascular Remodeling And Therapeutic Effect Of Losartan

Objective:To study the role of vascular peroxidas in vascular remodeling of hypertensive rats and investigate whether Losartan inhibit vascular remodeling via VPO1/MMPs pathway.Methods:1. Thirty-six male spontaneously hypertensive rats (12-week-old) were randomly divided into three groups hypertensive group (SHR group), low-dose Losartan treatment group (Losartan10mg/kg/day, po), High-dose Losartan treatment group (Losartan30mg/kg/day, po) and the same age Wistar-Kyoto rats as control group (WKY group). Blood pressure was measured once a week, the rats were administrated for8weeks. Thoracic aortas and abdominal aortas of rats are stained by Hematoxylin-eosin (HE), VPO1expression was detected by immunohistochemical.Detected hydrogen level and activity were measured at the same time. Expression of MMP-2and MMP-9was measured by Western Blot.2.Cultured rat vascular smooth cells (VSMC), were treated with AngⅡ (10-6M) and different concentration of Losartan (10-5M,10-6M) for24h. Expressions of VPO1、MMP-2and MMP-9were measured by Real-Time PCR and Western Blot. H2O2and HOCl concentrations in VSMC were detected, too.3. VSMC model of VPO1shRNA was built successfully, and was treated by AngⅡ (100nM) for24h. Effect of VPO1shRNA in level of H2O2and HOC1expressions of MMP-2and MMP-9was observed.Results:1. The aortic walls of SHR group were more thick than any other groups. Sequences of VSMC in medial membrane were disorganized. The quantity of nuclei per unit area were increased. Moreover, expression of VPO1, MMP-2and MMP-9was increased in the remodeling vessels. Losartan can significantly reverse vascular remodeling with a dose-dependent manner, meanwhile it could inhibit VPO1, MMP-2and MMP-9expression. H2O2concentration and AngⅡ level was increased but CAT activity was decrease in SHR rats. Treatment of Losartan could decrease H2O2concentration and recover CAT activity2. Ang II (10-6M) could significantly promote the expressions of VPO1,MMP-2and MMP-9, increase the concentrations of H2O2and HOC1. Losartan could inhibit these effects with a dose-dependent manner.3. AngⅡ could increase H2O2level in VSMC with VPOi shRNA. However, HOC1, MMP-2, MMP-9level didn’t change.Conclusion:VPO1could lead to degradation of extracellular matrix and vascular remodeling of SHR rats via promotion of MMP-2and MMP-9overexpression. Losartan could reverse vascular remodeling via VPO1/HOC1/MMPs pathway.