Role Of Urotensin â…¡ In Arthrosclerosis And Vascular Remodeling After Injury

Objectives:1.To study the correlation between Urotensinâ…¡(Uâ…¡) concentration and the severity of coronary artery disease(CAD).2.To evaluate the exogenous UII's effection on injured vessel,especially the extracellular matrix response.In addition the effect of Urantide,a selective peptidic UT receptor antagonist,was assessed too.3.To evaluate the effection of Urotensinâ…¡on collagen synthesis and secretion in vitro.Methods:1.We studied UII concentrations in 100 patients with known or suspected CAD referred for coronary arteriography.Micheal score system was used to estimate the severity of CAD.2.Stenosis model of thoracic aorta 21 days after balloon injury was established in male Wistar rats,which were divided into 4 groups(n=5),including sham injured,injured,UII(1nmol/kg/h,infused by osmotic mini-pump) and Urantide(10nmol/kg/h) group.H-E staining and Masson-Trichrome staining were used for morphometric analysis,RT-PCR for the mRNA expressions and immunohistochemical staining assay for protein expression.3.Thoracic aortas were separated 7days and 14 days after balloon injury(4 rats per group) and treated with Urotensinâ…¡,collagen synthesis and secretion were measured by ³H-proline incorporation.Results:1.UII concentration was higher in severer group(score≥9) than in normal or nearly normal group(score＜3),(2.50±1.62ng/ml vs 1.61±1.05ng/ml,P=0.03) UII concentration correlated with CAD severity(r=0.213,P=0.034).By multiple regression analysis,UII is one determinant of the severity of CAD,other than age, abnormal glucose,hypertension and gender.2.â‘ Compared with sham injured vessel,UII was increased significantly in injured vessel,and GRP-14mRNA was upregulated.â‘¡In UII group GRP-14mRNA further upregulated,the intimal hyperplasia was markedly increased((13±5)%vs (7±2)%,P＜0.05),collagen content was also increased,typeâ… collagen increased 1 fold,typeâ…¢collagen decreased 64%,while no significant difference in mRNA levels was found.MMP-1 decreased significantly(3.33±0.82 vs 8.30±1.81,P＜0.05). MMP-2 activity increased 1.25 fold,TIMP-2 protein decreased by 73.3%.â‘¢In Urantide group,compared with injured group,GRP-14mRNA dowuregulated,the intimal hyperplasia didn't reduce((9±3)%vs(7±2)%,P＞0.05),collagen protein and mRNA had no difference,MMP-1 protein had no significant difference,the activity of MMP-2 increased 1.29 fold,TIMP-2 protein decreased by 55.4%.3.UII stimulated the collagen synthesis in non-injured vessel in a concentration-dependent manner.In aorta 7days after balloon injury,the collagen synthesis increased by 87.7%,81.2%,56.8%(all P＜0.05) than in non-injured vessel stimulated by 10^-10,10^-9 and 10^-8mol/l UII respectively,and collagen secretion increased by 34.6%,17.5%and 17.2%(all P＜0.05).The synthesis and secretion increase 14 days later is less than that of 7days later.Conclusions:1.UII is elevated in severe CAD and there is a significant relationship between UII concentration and CAD severity.2.In injured vessel,UII expression increases,and GRP-14 mRNA upregulates.Exogenous UII stimulates GRP-14 mRNA upregulation,collagen accumulation,and increases MP-2/TIMP-2 rate which may prolong vascular remodeling contributing to intimal hyperplasia.Urantide(10nmol/kg/h) can antagonize GRP-14mRNA upregulation,but has no effect on collagen accumulation and has a similar tendency on MMP-2/TIMP-2 balance,so in present study,Urantide has no protective effect on blood vessel stenosis.