Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease.
OBJECTIVE
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 up-regulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes.


RESULTS
During 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).


CONCLUSIONS
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.
Chung
Ada W Y
AW
Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4. adawingyee@yahoo.ca
Yang
H H Clarice
HH
Sigrist
Mhairi K
MK
Brin
Genevieve
G
Chum
Elliott
E
Gourlay
William A
WA
Levin
Adeera
A
D000328:Adult; D000368:Aged; D043168:Angiostatins / Q000378:metabolism; D001158:Arteries / Q000378:metabolism* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000378:metabolism; D016022:Case-Control Studies; D002908:Chronic Disease; D015331:Cohort Studies; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D004548:Elasticity / Q000502:physiology*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D010710:Phosphates / Q000378:metabolism; D012307:Risk Factors
D010710:Phosphates; D043168:Angiostatins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9