Effects Of ERK And AT₁ R On The Release Of PAI-1 In Vascular Smooth Muscle Cells Induced By Angiotension Ⅱ In Hypertensive Rats And Intervention With Telmisartan

OBJECTIVE To investigate the expression of extracellular signal-regulated kinase(ERK)and angiotensinⅡ(AngⅡ)type 1 receptor(AT1R)protein and the release of plasminogen activator inhibitor-1(PAI-1)induced by AngⅡ as well as the receptor and signal transduction pathways that involve in the release of PAI-1 in vascular endothelial cells(VEC)and vascular smooth muscle cells(VSMC)of experimental hypertensive rats,and to explore the effect and mechanism of telmisartan on improving fibrinolytic activity of experimental hypertensive rats. METHODS Animal model of experimental hypertensive rats was achieved by partially banding abdominal aortic artery.24 Sprague-Dawley rats were randomly divided into three groups:①sham-operated group(control group, n=8),②abdominal aorta constriction group(hypertension group,n=8),③telmisartan group(n=8).Experimental hypertensive rats in telmisartan group were treated with telmisartan(3㎎·㎏-1·d-1) dissolved in drinking water from second week to fifth week and the other rats in hypertension group and control group were received plain drinking water.Plasma and aorta AngⅡlevel were measured by radioimmunoassay while tissue type plasmingen activator(t-PA) and PAI-1 activity in plasma and aorta was determined by spectrophotometric assay.The expression of ERK and AT1R protein in VEC and VSMC were examined by immunohistochemistry.　RESULTS ⑴Compared with control group,t-PA and PAI-1 activity in plasma and aorta were decreased and increased in hypertension group repectively(P<0.05),and fibrinolytic function was depressed.⑵In hypertension group plasma AngⅡlevel,plasma PAI-1 activity,ERK and AT1R expression in VSMC were increased(P<0.05).There was an obviously positive correlation among plasma AngⅡlevel, plasma PAI-1 activity, ERK and AT1R expression in VSMC(r=0.89～0.96, P<0.01～0.001). Aortic AngⅡlevel and PAI-1 activity of aorta and ERK and AT1R expression of VSMC in hypertension group were higher than those in control group(P<0.05).AngⅡlevel in aorta was positive relation to PAI-1 activity in cultured vessls isolated from aorta and expressing of ERK and AT1R protein in VSMC(r=0.86～0.96, P<0.01～0.001).⑶Compared with hypertension group,ERK and AT1R protein expressing of VSMC and VEC were significantly reduced in telmisartan group(P<0.05).The release of PAI-1 in isolated aorta and the activity of plasma PAI-1 were obviously lowered(P<0.05),and the release of aorta t-PA and the activity of plasma t-PA as well as the ratio of t-PA/PAI-1 were remarkably increased by telmisartan on the other hand(P<0.05),suggesting that telmisartan can effectively improve fibrinolytic parameters of experimental hypertensive rats.　CONCLUSIONS ⑴In hypertensive rats the activity of plasma t-PA was decreased and the activity of plasma PAI-1 was increased and fibrinolytic function was lowered.⑵The increased plasma PAI-1 activity was associated to plasma AngⅡlevel.The lowered fibrinolytic function in hypertension may be attributed to the enhancement of the biosynthesis and release of PAI-1 from VSMC by higher concentration of plasma AngⅡ,which is likely dependent on an AT1R mediated activation of ERK in VSMC.⑶Telmisartan can significantly improve impaired fibrinolysis of experimental hypertensive rats.⑷Telmisartan could suppress the expression of ERK and AT1R in VSMC and VEC that may play a critical role in the downregulation of PAI-1 activity induced by AngⅡ,which may be correlated with improvement of fibrinolytic function.