组织基质金属蛋白酶抑制剂-1与尿毒症血管中膜钙化

MMP-9 and TIMP-1 are associated with vascular medial calcification in uremic patients

目的研究终末期尿毒症患者桡动脉血管壁上基质金属蛋白酶及其抑制剂表达与钙盐沉积的关系,探讨基质金属蛋白酶及其抑制剂是否参与血管钙化。方法选择大连医科大学附属第一医院肾内科80例尿毒症患者的桡动脉为尿毒症组;10例因上肢外伤行截肢手术时取得桡动脉为正常对照组。HE染色观察血管;应用von Kossa染色判断钙盐沉积程度;应用免疫组化方法测定uMP-9、TIMP-1、骨桥蛋白(OPN)、I型胶原、核心结合因子(Cbfa1)在血管壁上的表达;同时测定外周血中钙、磷、三酰甘油(TG)、总胆固醇(Tch)、低密度脂蛋白(LDL)、白蛋白(ALB)、血红蛋白(Hb)、甲状旁腺激素(iPTH)、C反应蛋白(CRP)。结果80例尿毒症桡动脉血管标本中出现血管钙化36例,发生率45%;其中轻中度钙化25例,重度钙化11例,钙化均发生在血管中膜。钙化的血管中膜均有MMP-9、TIMP-1、OPN、I型胶原、Cbfa1的阳性表达(P<0.01),无钙化的44例血管中有33例血管中膜有OPN的表达,29例有I型胶原的表达,但无Cbfa1的阳性表达。对照组血管均无中膜钙化表现,亦无OPN表达。两组患者的体重指数、血钙、三酰甘油(TG)、总胆固醇(Tch)、低密度脂蛋白(LDL)、白蛋白(ALB)差异无统计学意义。尿毒症患者的平均收缩压、血磷水平、钙磷乘积、iPTH、C反应蛋白水平明显高于对照组(P<0.01)。血红蛋白水平明显低于对照组(P<0.01)。结论尿毒症患者普遍存在血管钙化,uMP-9、TIMP-1在尿毒症患者桡动脉的血管壁表达和血管钙化程度相关,提示组织基质金属蛋白酶系统在尿毒症血管钙化中可能有重要作用。

Objective To study the relationship between the medial calcification of arteries and the expressions of matrix metallopeptidase 9 （MMP-9） and tissue inhibitor of metalloproteinase 1 （TIMP-1） in uremic patients. Methods Pieces of radial arteries were taken from 80 uremic patients at the time of arteriovenous fistula operation. The control radial arteries were taken from trauma patients with normal kidney function at the time of amputation operation. Vascular calcification was evaluated histomorphometrically on Von Kossa-stained sections, and the expressions of MMP-9, TIMP-1, osteopontin （OPN）, collagen I, core binding factor a-1 （Cbfa-1） were determined immunohistochemically. Other related factors including serum calcium, phosphate, cholesterol, triglyceride （TG）, lowdensity lipoproteins （LDL）, albumin （ALB）, hemoglobin （Hb）, intact parathyroid hormone （iPTH） and C-reactive protein （CRP） were also detected. Results Vascular calcification was found in 36 uremic patients （45%）, while no vascular calcification in the control group. Mild to moderate calcification was found in 25 uremic patients, and severe calcification in 11 cases. All of the radial arteries with calcification showed positive immunostaining of MMP-9, TIMP- 1, OPN, collagen I and Cbfal （p〈0.01）. In some uremic radial arteries without morphologically obvious calcification, immunostaining of OPN and collagen I were also positive, but immunostaining of Cbfal was negative. Mean arterial blood pressure, serum phosphate, serum calcium-phosphate product, serum iPTH and CRP were significantly higher in uremic patients than in controls （p 〈 0.01）, but body mass index, serum calcium, TG, total cholesterol, LDL and ALB had no differences between the two groups. Conclusion We have demonstrated, for the first time, that expressions of MMP-9 and TIMP-1 in arteries are correlated to vascular calcification in uremic patients. Our results suggest that the imbalance expression of MMP-9/TIMP-1 may cause, at least partially, vascular medial calcification in uremic patients.