Matrix metalloproteinase-2 and-9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease

Abstract

AimsChronic kidney disease (CKD) and diabetes are the prominent risk factors of cardiovascular disease (CVD). Matrix metalloproteinase (MMP)-2 and-9 regulate vascular structure by degrading elastic fibre and inhibit angiogenesis by generating angiostatin. We hypothesized that MMP-2 and-9 were up-regulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes.Methods and resultsDuring living donor transplantation procedures, arteries from donors (n = 8) and recipients (non-diabetic, n = 8; diabetic, n = 8; matched in age, gender, and dialysis treatments) were harvested. Diabetic arteries had increased MMP-2 and-9 activities by 42 and 116 compared with non-diabetic ones. Diabetic arteries were the stiffest, and the stiffness measurement was highly correlated with the summation of MMP-2 + MMP-9 activities (r = 0.738, P = 0.0002). Pulse wave velocity measurements correlated with MMP activity (r = 0.683, P = 0.005). Elastic fibre degradation and calcification were worst in diabetic vessels. The phosphate level, which was 25 higher in diabetic patients, correlated with MMP activity (r = 0.513, P = 0.04) and in vitro stiffness (r = 0.545, P = 0.03), respectively. Angiostatin expression was doubled, whereas vascular endothelial growth factor was 50 reduced in diabetic compared with non-diabetic vessels. Microvascular density in diabetic vessels was 48 of that in non-diabetic ones, and it was strongly associated with MMP activity (r =-0.792, P < 0.0001) and vasorelaxation (r = 0.685, P = 0.0009).ConclusionUsing a matched case-control design, we report up-regulation of MMP-2 and-9 in diabetic CKD arteries and correlate those with stiffening, impaired angiogenesis, and endothelial dysfunction. These findings may help to explain the high susceptibility of CVD in diabetic and non-diabetic CKD patients.