Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Son, Bo‐Kyung; Akishita, Masahiro; Iijima, Katsuya; Eto, Masato; Ouchi, Yasuyoshi

doi:10.5551/jat.e545

Cited by 30 publications

(14 citation statements)

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“…Statins, potent lipid lowering agents, have been shown to exert antioxidant effects and improve endothelial function in uremic animals [10] and in maintenance hemodialysis (HD) patients [11]. Statins have also been shown to have antithrombotic properties [12] and to prevent vascular calcification in experimental models [13]. However, it is not known whether these properties enable statins to offer any protection against the CUA development.…”

Section: Introductionmentioning

confidence: 99%

Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study

et al. 2013

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Background: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has shown that statins have anticalcification, antithrombotic and antiinflammatory properties; however, the association between statin use and CUA has not been investigated. Methods: This matched case-control study included 62 adult maintenance hemodialysis (HD) patients with biopsy-confirmed CUA diagnosed between the years 2002 and 2011 (cases). All cases were hospitalized at the time of diagnosis. Controls (n = 124) were hospitalized maintenance HD patients without CUA (matched to cases by gender and timing of hospitalization). Univariate and multivariable logistic regression models were applied to compute odds ratio (OR) and 95% confidence intervals (CI) for CUA in statin users, and also to examine previously described associations. -Results: The mean age of cases was 58 years. Most were females (68%), and of white race (64%). Statin use was more common in controls than in cases (39 vs. 19%, p < 0.01). Statin use was associated with lower odds of CUA in unadjusted (OR 0.38, 95% CI 0.18-0.79) and adjusted (OR 0.20, 95% CI 0.05-0.88) analyses. Hypercalcemia (OR 2.25, 95% CI 1.14-4.43), hypoalbuminemia (OR 5.73, 95% CI 2.79-11.77), calcitriol use (OR 5.69, 95% CI 1.02-31.77) and warfarin use (OR 4.30, 95% CI 1.57-11.74) were positively associated with CUA in adjusted analyses whereas paricalcitol and doxercalciferol were not (OR 1.33, 95% CI 0.54-3.27). Conclusion: Statin use may be negatively associated with odds of CUA. Further large prospective studies with attention to potential confounders are needed to confirm these findings.

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Section: Introductionmentioning

confidence: 99%

Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study

et al. 2013

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“…(1,(5)(6)(7)(8)(12)(13)(14)(15)(16)(17)(18) Our results are the first to relate DNA methylation with the loss of smooth muscle lineage marker SM22a in VSMCs incubated with high phosphate. SM22a promoter methylation decreases SM22a gene expression, and this fact could facilitate phenotypic transition of VSMCs to osteoblast-like cell.…”

Section: Discussionmentioning

confidence: 72%

“…A number of studies have shown that VCs are a well-regulated process that involves transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells capable of synthesizing the proteins required for calcification. (5)(6)(7) High phosphate concentration seems to play an essential role in the calcification process. In vitro studies have demonstrated that phosphate transport into the cell is a necessary step for calcification.…”

Section: Introductionmentioning

confidence: 99%

“…In vitro studies have demonstrated that phosphate transport into the cell is a necessary step for calcification. (1,5,6,8,9) Phenotypic transition from VSMCs to osteoblasts requires the loss of smooth muscle-specific proteins such as SM22a and the gain of osteochondrogenic differentiation markers such as core binding factor 1 (Cbfa1), a pivotal transcriptional regulator of osteoblast function. (7,10) One of the mechanisms by which cells can modify protein expression is by gene silencing through methylation of promoters.…”

Section: Introductionmentioning

confidence: 99%

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High-phosphate-induced calcification is related to SM22α promoter methylation in vascular smooth muscle cells

Madueño

Martínez-Moreno

et al. 2010

Journal of Bone and Mineral Research

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Hyperphosphatemia is closely related to vascular calcification in patients with chronic kidney disease. Vascular smooth muscle cells (VSMCs) exposed to high phosphate concentrations in vitro undergo phenotypic transition to osteoblast-like cells. Mechanisms underlying this transdifferentiation are not clear. In this study we used two in vitro models, human aortic smooth muscle cells and rat aortic rings, to investigate the phenotypic transition of VSMCs induced by high phosphate. We found that high phosphate concentration (3.3 mmol/L) in the medium was associated with increased DNA methyltransferase activity and methylation of the promoter region of SM22a. This was accompanied by loss of the smooth muscle cell-specific protein SM22a, gain of the osteoblast transcription factor Cbfa1, and increased alkaline phosphatase activity with the subsequent in vitro calcification. The addition of a demethylating agent (procaine) to the high-phosphate medium reduced DNA methyltransferase activity and prevented methylation of the SM22a promoter, which was accompanied by an increase in SM22a expression and less calcification. Additionally, downregulation of SM22a, either by siRNA or by a methyl group donor (S-adenosyl methionine), resulted in overexpression of Cbfa1.In conclusion, we demonstrate that methylation of SM22a promoter is an important event in vascular smooth muscle cell calcification and that high phosphate induces this epigenetic modification. These findings uncover a new insight into mechanisms by which high phosphate concentration promotes vascular calcification. ß

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“…Vascular calcification is one form of arteriosclerosis, and vascular calcification, which has been associated with osteochondrogenic differentiation of vascular smooth muscle cells [3,4,5], is considered to have some points in common to physiological calcification of the bone. It has been reported that serum phosphate induces vascular smooth muscle cell apoptosis and osteochondrogenic differentiation [4,6], and that serum phosphate levels are considered to be associated with vascular calcification [7,8,9]. In CKD patients, chronic inflammation and accelerated oxidative stress are common, and can also induce vascular calcification [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Analysis of Abdominal Aortic Calcification in CKD Patients Without Dialysis Therapy by Use of the Agatston Score

Ichii¹,

Ishimura²,

Shima³

et al. 2013

Kidney Blood Press Res

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Background/Aim: The aim of the present study was to quantitatively examine factors associated with aortic calcification in non-dialysis CKD patients. Methods: We quantitatively investigated aortic calcification from the renal artery to the bifurcation in 149 non-dialysis CKD patients (58±16 years; 96 males and 53 females, 48 diabetics; eGFR 40.3±29.3 ml/min), and measured Agatston scores using multi-slice computed tomography. Result: Of 149 patients, aortic calcification was present in 117. In patients with aortic calcification, age (p<0.001), C-reactive protein (p<0.001), and intact-PTH (p < 0.001) were significantly higher, estimated glomerular filtration rate (eGFR) was significantly lower (p<0.001), and diabetes was observed more often (p<0.05). In regards to the degree of aortic calcification, the Agatston scores correlated significantly and positively with age (ρ=0.438, p<0.001) and serum phosphate (ρ=0.208, p=0.024), and correlated significantly but negatively with e-GFR (ρ=-0.353, p<0.001). In multiple regression analysis, eGFR was associated significantly and independently with the log [Agatston score] (β=-0.346, p<0.01), after adjustment for several confounders including serum phosphate and the presence of diabetes. Conclusions: Hyperphospatemia, chronic inflammation, diabetes, and decreased GFR are associated significantly with the presence of aortic calcification in non-dialysis CKD patients. Decreased eGFR was associated significantly and independently with the quantitative degree of aortic calcification.

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Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Cited by 30 publications

References 50 publications

Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study

Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study

High-phosphate-induced calcification is related to SM22α promoter methylation in vascular smooth muscle cells

Quantitative Analysis of Abdominal Aortic Calcification in CKD Patients Without Dialysis Therapy by Use of the Agatston Score

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