MMP-9 And TIMP-1 Are Associated With Artery Calcification In Uremic Patients

Background and Objective:Cardiovascular diseases(CVD) are the major cause of morbidity and mortality in patients on hemodialysis. Recent studies have demonstrated that the process of vascular calcification resembles developmental osteogenesis. The progress of vascular calcifica-tion(VC) is characterized by the deposition of calcium salts which dependent upon the controlling of extracellular matrix metabolism. The aim of this study is to investigate whether the medial artery calcification correlated with the expressions of MMP-9 and TIMP-1 in uremic patients to attemp to provide a new clue for mechanism of VC.Methods:Pieces of depleted radial arteries were taken from 80 uremic patients at the time of the arteriovenous fistula operation. The control radial arteries were taken from trauma patients with normal kidney function at the time of the amputation operation. Vascular calcification was evaluated histomorphometrically on Von Kossa-stained sections, and the expressions of the matrix metalloproteinase-9 (MMP-9),tissue inhibitor of metalloproteinase-1 (TIMP-1),osteopontin(OPN),collagenâ… ,core binding factor a-1(Cbfa-1) were determined immunohistochemically. The serum level of matrix metallo-proteinase inhibitor were determined by enzyme-linked immunosorbentassay(ELISA) in 60 uremic patients as well as in 60 controls with normal renal function. Quantification of CAC was determined by multilayer spiral CT scan and to evaluate the degree of CAC by calcification score. Other related factors including serum calcium, phosphate, total cholesterol(TC), triglyceride(TG), low-density lipoprotein (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 calcification occurred in medial layer. All of the radial arteries with calcification showed positive immunostaining of MMP-9,TIMP-1,OPN,Collagenâ… and Cbfa-1 (P<0.01). In some uremic radial arteries without morphologically obvious calcification, immunostaining of OPN and Collagenâ… were also positive, but immunostaining of Cbfa-1 was negative. The mean calcification score was 783.27, and 47 patientes(78.33%) had CAC. However, the mean calcification score was 2.2 in control and only 5 had CAC. Mean arterial blood pressure, serum phosphate, seru mcalcium-phosphorus product, serum iPTH, CRP and serum TIMP-1 were significantly higher in uremic patients than in controls (P<0.01), but body mass index, serum calcium, TC, TG, LDL and ALB had no differences between the two groups. The levels of HB in uremic patients were significantly lower than in controls (P<0.01). Age, body mass index, the proportion of diabetes, duration of hemodislysis, serum phosphate, calcium-phosphorus product, CRP, TC and LDL in CAC patients were significantly higher than in NCAC (P<0.01).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.