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(Circulation. 2009;120:792-801.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Upregulation of Matrix Metalloproteinase-2 in the Arterial Vasculature Contributes to Stiffening and Vasomotor Dysfunction in Patients With Chronic Kidney Disease

Ada W.Y. Chung, PhD; H.H. Clarice Yang, MSc; Jong Moo Kim, BSc; Mhairi K. Sigrist, PhD; Elliott Chum, MD; William A. Gourlay, MD; Adeera Levin, MD

From the Department of Cardiovascular Science, Child and Family Research Institute (A.W.Y.C., H.H.C.Y., J.M.K.), Divisions of Nephrology (M.K.S., E.C., A.L.), and Urologic Science (W.A.G.), University of British Columbia, Vancouver, British Columbia, Canada.

Correspondence to Ada W.Y. Chung, PhD, Cardiovascular Science, Room 2099, 950 28th W Ave, Vancouver, British Columbia, Canada V5Z 4H4. E-mail adawingyee{at}yahoo.ca

Received January 6, 2009; accepted June 15, 2009.

Background— Cardiovascular disease is the leading cause of mortality in chronic kidney disease patients on maintenance dialysis. Given the importance of matrix metalloproteinase-2 (MMP-2) in matrix integrity, vascular cell function, and structural stability, we hypothesized that MMP-2 was elevated in the macrovasculature in dialyzed chronic kidney disease patients compared with chronic kidney disease patients not on dialysis and kidney donors.

Methods and Results— Arteries from live kidney donors (A_donor; n=30) and recipients (nondialysis [A_nondialyzed], n=17; dialysis [A_dialyzed], n=23 [peritoneal dialysis, n=10; hemodialysis, n=13]) were harvested during the transplantation procedure. Compared with A_donor, MMP-2 upregulation was evident in both recipient groups. Protein expression of latent plus active MMP-2 in A_dialyzed was 2-fold that in A_nondialyzed. MMP-2 activity increased with length of dialysis (r=0.573, P=0.004). In A_dialyzed, medial elastic fiber fragmentation was pronounced, and the ratio of external elastic lamina to media was negatively correlated with MMP-2 activity (r=–0.638, P=0.001). A_dialyzed was 25% stiffer than A_nondialyzed; this increased stiffness correlated with MMP-2 activity (r=0.728, P<0.0001) and the severity of medial calcium deposition (r=0.748, P=0.001). The contractile function and endothelium-dependent relaxation were reduced by 35% to 55% in A_dialyzed and were negatively associated with MMP-2 activity (r=–0.608, P=0.002; r=–0.520, P=0.019, respectively). Preincubation with MMP-2 inhibitor significantly improved contractility and relaxation in A_dialyzed.

Conclusions— We describe a strong correlation between MMP-2 activation and elastic fiber disorganization, stiffness, calcification, and vasomotor dysfunction in the arterial vasculature in dialyzed chronic kidney disease patients. These findings may contribute to an improved understanding of mechanisms important in vascular health in chronic kidney disease patients.

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Circulation 2009 120: 717. [Extract] [Full Text]