Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

Abstract

Background/Aims: Matrix metalloproteinases (MMPs), their inhibitors (TIMPs), oxidative stress (SOX) and kynurenine (KYN) pathway have been postulated in cardiovascular disease (CVD) progression. We hypothesized the possible association between the MMP/TIMP system, KYNs and CVD prevalence in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: We assessed MMP-2, MMP-9, TIMP-1, TIMP-2, KYN and its metabolite – quinolinic acid (QA), and SOX marker – Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in CAPD patients both with and without CVD and healthy controls. Results: MMP-2, TIMP-2, Cu/Zn SOD, KYN and QA were significantly higher in CAPD patients with CVD than in patients without CVD and controls. MMP-2 and TIMP-2 were positively correlated with QA and Cu/Zn SOD levels, and the strong association was between MMP-2 and TIMP-2 levels. Multiple regression analyses identified Cu/Zn SOD, TIMP-2, QA and QA/KYN ratio as the factors independently associated with MMP-2, whereas MMP-2 and Cu/Zn SOD were independent variables affecting TIMP-2 levels. Conclusions: MMP-2 and TIMP-2 concentrations were higher in CAPD patients with CVD than in patients without CVD and healthy controls. Upregulation of the MMP-2/TIMP-2 system was associated with QA levels and increased oxidative status, suggesting the connection between KYN pathway activation, arterial remodeling and CVD prevalence in uremic patients on CAPD treatment.

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

“…In line with our results showing increased MMP-2 and TIMP-2 levels in ESKD patients, elevated circulating MMP-2 and TIMP-2 levels have been described as an indicator of CVD in dialysis patients [8,9]. It is possible that TIMP-2 levels increase in order to protect against abnormal proteolytic activity in patients on dialysis, which could promote excessive extracellular matrix remodeling, as previously suggested [9,15]. While most of the previous studies agree with our findings [8,10,11,12], two studies detected no significant changes in these markers [13,14], and one study showed lower TIMP-2 levels and augmented MMP-2/TIMP-2 ratios in ESKD [14].…”

“…These alterations clearly promote vascular medial layer calcification [6], and the increases in MMP-2 levels correlated positively with vascular stiffness and phosphate concentrations in chronic kidney disease patients [25]. In line with our results showing increased MMP-2 and TIMP-2 levels in ESKD patients, elevated circulating MMP-2 and TIMP-2 levels have been described as an indicator of CVD in dialysis patients [8,9]. It is possible that TIMP-2 levels increase in order to protect against abnormal proteolytic activity in patients on dialysis, which could promote excessive extracellular matrix remodeling, as previously suggested [9,15].…”

“…While growing evidence suggests that MMP abnormalities are involved in the vascular changes associated with kidney failure [6], a particular imbalance between MMP-2 and its endogenous inhibitor, TIMP-2, has been implicated in the vascular alterations of ESKD[7]. Previous studies showed altered MMP-2 and TIMP-2 levels in dialysis patients, thus suggesting a mechanism for cardiovascular disease (CVD) complications in these patients [8,9,10,11,12]. However, inconsistent results have been reported with respect to the effects of hemodialysis on the circulating MMP levels.…”

Decreases in plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in uremic patients during hemodialysis

“…These alterations clearly promote vascular medial layer calcification and the increases in MMP-2 level correlated positively with vascular stiffness and phosphate concentrations in CKD patients [8]. In line with our results showing increased MMP-2 level in uremic patients, the elevated circulating MMP-2 levels have also been described as an indicator of cardiovascular disease in HD patients [13,24]. Compared to MMP-2, very conflicting results on MMP-9 level in progressive CKD and ESKD patients have been reported (Table 5).…”

“…Among known MMPs, gelatinases (MMP-2, 72 kDa; MMP-9, 92 kDa) are the most studied because accumulated data show that both enzymes play important roles in the pathogenesis of cardiovascular diseases and CKD [4,8]. TIMPs (21)(22)(23)(24)(25)(26)(27)(28) are specific endogenous molecule that bind MMPs and inhibit MMPs activity [2]. TIMP-1, -2, -3 and -4, have been identified in humans and their expression is regulated during development and tissue remodeling [10].…”