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

Ada W.Y. Chung, H.H. Clarice Yang, Mhairi K. Sigrist, Genevieve Brin, Elliott Chum, William A. Gourlay, Adeera Levin
2009 Cardiovascular Research  
Aims Chronic 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 upregulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes. Methods and results During living donor transplantation procedures, arteries from donors (n
more » ... ries from donors (n ¼ 8) and recipients (non-diabetic, n ¼ 8; diabetic, n ¼ 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 þ MMP-9 activities (r ¼ 0.738, P ¼ 0.0002). Pulse wave velocity measurements correlated with MMP activity (r ¼ 0.683, P ¼ 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 ¼ 0.513, P ¼ 0.04) and in vitro stiffness (r ¼ 0.545, P ¼ 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 ¼ 20.792, P , 0.0001) and vasorelaxation (r ¼ 0.685, P ¼ 0.0009). Conclusion Using 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.
doi:10.1093/cvr/cvp242 pmid:19617223 fatcat:itngkq7lfrfenh7h4szcvtqnfq