Activation of Arterial Matrix Metalloproteinases Leads to Vascular Calcification in Chronic Kidney Disease

Chen, Neal X.; O’Neill, Kalisha D.; Chen, Xianming; Kiattisunthorn, Kraiwiporn; Gattone, Vincent H.; Moe, Sharon M.

doi:10.1159/000330175

Cited by 82 publications

(79 citation statements)

References 40 publications

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“…Interestingly, experimental evidence showed an early upregulation of MMP-2 expression in areas of elastin degradation and smooth muscle cells phenotype change in chronic kidney disease course, which is associated with increased circulating MMP-2 levels [4,5,6]. These alterations clearly promote vascular medial layer calcification [6], and the increases in MMP-2 levels correlated positively with vascular stiffness and phosphate concentrations in chronic kidney disease patients [25]. In line with our results showing increased MMP-2 and TIMP-2 levels in ESKD patients, elevated circulating MMP-2 and TIMP-2 levels have been described as an indicator of CVD in dialysis patients [8,9].…”

Section: Discussionmentioning

confidence: 99%

“…This process includes enhanced arterial calcification and activation of fibroblasts and cytokines, eventually leading to vascular extracellular matrix remodeling [4,5]. While growing evidence suggests that MMP abnormalities are involved in the vascular changes associated with kidney failure [6], a particular imbalance between MMP-2 and its endogenous inhibitor, TIMP-2, has been implicated in the vascular alterations of ESKD[7]. Previous studies showed altered MMP-2 and TIMP-2 levels in dialysis patients, thus suggesting a mechanism for cardiovascular disease (CVD) complications in these patients [8,9,10,11,12].…”

Section: Introductionmentioning

confidence: 99%

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Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Marson¹,

Lacchini²,

Belo³

et al. 2012

Am J Nephrol

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Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C^–1306T and C^–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C^–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C^–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Marson¹,

Lacchini²,

Belo³

et al. 2012

Am J Nephrol

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“…[11][12][13][14] As well as leading to a loss of arterial compliance, per se, elastin degradation also appears to be a precursor to mineralization, 15 priming the vessel wall for calcification through the release of elastin peptide fragments (or elastinderived peptides [EDPs]) that induce osteogenic responses in VSMCs 16 and by providing a nidus for mineral crystal growth. Because there is now strong evidence that elastin degradation may play an important role in vascular disease, we hypothesized that higher circulating cathepsin S, MMP-2, and EDP levels would be associated with increased mortality in our cohort of 200 patients with predialysis CKD.…”

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confidence: 99%

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

et al. 2012

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Abstract-In the large conduit arteries, elastin is important in maintaining vascular compliance. Studies in animal models suggest that elastin degradation may promote arteriosclerotic vascular changes. There is already a well-established link between aortic stiffening and mortality in the general population and in patients undergoing dialysis. Elastin degradation is mediated by several proteases, including matrix metalloproteinase 2 and cathepsin S. Elastin turnover may be inferred by measuring serum levels of elastin-derived peptides. We analyzed the serum concentration of these biomarkers, their endogenous inhibitors, and aortic pulse wave velocity in 200 patients with stages 3 and 4 chronic kidney disease and then serially in a subgroup of 65 patients over 36 months. Serum matrix metalloproteinase 2, cathepsin S, and elastin-derived peptide levels were independently associated with baseline aortic pulse wave velocity and changes in stiffness over the follow-up period. Higher matrix metalloproteinase 2 and elastin-derived peptide levels were also independently associated with preexisting cardiovascular disease. In multivariable Cox regression, higher serum elastin-derived peptide levels were independently associated with increased all-cause mortality (hazard ratio per SD increaseϭ1.78; Pϭ0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality. 1 Loss of elastin leads to an increase in the collagen:elastin ratio and augmented mechanical loading of stiffer collagen fibers. With age, vascular smooth muscle cells (VSMCs) become less contractile, and there are increased rates of cellular senescence and death.2 Together, these changes contribute to the loss of intrinsic elasticity and progressive stiffening of the arterial wall.3 In addition to promoting arteriosclerosis, elastin degradation also stimulates intimal VSMC invasion, neointima formation, and plaque destabilization and, thus, may also be an important factor in the pathogenesis of atherosclerotic disease. Age-associated arterial remodeling is accelerated in patients with chronic kidney disease (CKD), who have a vastly elevated cardiovascular risk compared with the general population. 5 Although not a universal finding, arterial stiffness, as measured by various methods, has been associated with decline in renal function in patients with CKD 6-8 and is a strong predictor of cardiovascular risk and all-cause mortality in patients with end-stage renal failure 9 and in non-CKD populations. 10Extracellular matrix turnover is mediated by a number of elastolytic proteinases, including Zn 2ϩ /Ca 2ϩ -dependent matrix metalloproteinases (MMPs; eg, MMP-2) and cathepsin cysteine proteases, such as cathepsin S. These proteases are mainly secreted by activated macrophage, resident myofibroblasts, or VSMCs but are also expressed intracellularly in a wide range of cell types. 4 The activities of MMP-2 and cathepsin S are partly regulated by the concentration of endog...

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“…30) Furthermore, lumican-transfected pancreatic cancer cells were reported to secret 70 kDa lumican (KS-GAG-rich lumican) and to decrease the production of MMP-9.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Glycosylation of Lumican in Aortic Valve Stenosis Revealed by Proteomic Analysis

et al. 2016

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SummaryTo identify proteins related to the pathophysiology of aortic valve stenosis (AS), we investigated the protein profiles of AS aortic valves. Specifically, proteins were extracted from a thickened and calcified area (AS-C) and an apparently non-thickened and non-calcified area (AS-N) in an identical aortic valve leaflet in each of 6 AS patients. The proteins were then separated by 2-dimensional gel electrophoresis (2DE). Protein spots detected by 2DE were compared between the AS-C and AS-N samples. Protein spots of interest were subjected to protein identification by mass spectrometry.In total, 670 protein spots were detected by 2DE, 28 of which showed more than 1.5-fold different intensity (P < 0.05) between the AS-C and AS-N samples. Proteins were identified in 17 out of the 28 spots. Fibrinogen and lumican were identified in 9 and 3 spots, respectively. Intensity of these 12 spots was lower in the AS-C samples than in the AS-N samples. In the 1D-Western blot analysis, 4 lumican bands (80 kDa, 75 kDa, 65 kDa, and 53 kDa) were detected, of which 2 bands with 80 kDa and 75 kDa showed lower intensity in the AS-C samples than in the AS-N samples. When de-glycosylated protein samples were used in the 1D-Western blot, only a single lumican band with ~40 kDa was detected, indicating that lumican was variously glycosylated and that highly glycosylated lumican molecules were decreased in AS-C.Collectively, insufficient glycosylation of lumican in the thickened and calcified areas of AS aortic valves may be involved in the pathophysiology of AS. (Int Heart J 2016; 57: 104-111) Key words: Calcification, 2-dimensional gel electrophoresis, Mass spectrometry, Peptide:N-glycosidase F, Proteoglycan A ortic valve stenosis (AS) is one of the most common cardiovascular diseases. Several decades ago, the main cause of AS used to be rheumatic fever, however, it was recently replaced by degenerative changes with calcification.

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Activation of Arterial Matrix Metalloproteinases Leads to Vascular Calcification in Chronic Kidney Disease

Cited by 82 publications

References 40 publications

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

Aberrant Glycosylation of Lumican in Aortic Valve Stenosis Revealed by Proteomic Analysis

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