Cardiovascular Research Advance Access first published online on July 17, 2009
This version [Corrected Proof] published online on August 3, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp242
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Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease
1 Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Room 2099, 950 28th W Ave, Vancouver, BC, Canada V5Z 4H4
2 Division of Nephrology, University of British Columbia, Vancouver, Canada
3 Division of Urologic Science, University of British Columbia, Vancouver, Canada
* Corresponding author. Tel: +1 604 875 3852; fax: +1 604 875 3120. E-mail address: adawingyee{at}yahoo.ca
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 up-regulated 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 = 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).
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.
KEYWORDS Chronic kidney disease; Diabetes; Matrix metalloproteinase; Angiogenesis; Endothelial dysfunction
Time for primary review: 16 days