title: Upregulation of matrix metalloproteinase-2 in the arterial vasculature contributes to stiffening and vasomotor dysfunction in patients with chronic kidney disease.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. adawingyee@yahoo.ca
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Chung
authors.forename: H H Clarice
authors.initials: HH
authors.lastname: Yang
authors.forename: Jong Moo
authors.initials: JM
authors.lastname: Kim
authors.forename: Mhairi K
authors.initials: MK
authors.lastname: Sigrist
authors.forename: Elliott
authors.initials: E
authors.lastname: Chum
authors.forename: William A
authors.initials: WA
authors.lastname: Gourlay
authors.forename: Adeera
authors.initials: A
authors.lastname: Levin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D001158:Arteries / Q000201:enzymology* / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000473:pathology*; D004548:Elasticity; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000601:surgery / Q000628:therapy; D016030:Kidney Transplantation; D019520:Living Donors; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D006435:Renal Dialysis; D017540:Tunica Media / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; D011189:Potassium Chloride; D020778:Matrix Metalloproteinase 2; D000109:Acetylcholine