Role of 8-isoprostane, Matrix Gla Protein (MGP) and Bone Morphogenetic Protein-2 (BMP-2) in Vascular Calcification in Chronic Kidney Disease

Wiwik Rositawati, Syakib Bakri, Gatot Susilo Lawrence, Andi Wijaya


BACKGROUND: Vascular calcification may be an important risk factor of cardiovascular disease in Chronic Kidney Disease (CKD). The pathobiology of vascular calcification in CKD is complex and involves some factors including inflammation, oxidative stress and balancing of calcification regulators. The aim of the study was to investigate the interaction between 8-isoprostane with calcification regulators such as matrix gla protein (MGP) and bone morphogenetic protein (BMP)-2 with vascular calciication in CKD.

METHODS: A cross-sectional study was performed on 63 subjects undergoing haemodialysis maintenance for more than 3 months. Abdominal aortic calcification (AAC) was measured using a lateral abdominal X-ray for calcification in abdominal aorta, which is related to severity of calcific deposits at lumbar vertebral segment (L)1-L4. Serum levels of 8-isoprostane, MGP and BMP-2 were measured by enzyme-linked immunosorbent assay method.

RESULTS: Results showed that 8-isoprostane levels were correlated with BMP-2 (r=0.266, p=0.018) and MGP levels (r=0.410, p≤0.001). MGP/BMP-2 levels ratio was correlated with AAC score (r=0.279, p=0.013). Subjects were then stratified into 3 groups based on AAC score: 0, 1-6 and ≥7. The highest mean of MGP levels was in AAC score 1-6 group, and the highest mean of 8-isoprostane levels was in AAC score ≥7. In the group of AAC score 0, 8-isoprostane levels were correlated with MGP levels (r=0.499, p=0.001) and MGP/BMP-2 levels ratio (r=0.291, p=0.034). In AAC score 1-6 group, 8-isoprostane levels were correlated with BMP-2 (r=0.661, p=0.005) and MGP levels (r=0.569, p=0.017). In AAC score ≥7 group, MGP levels were positively correlated with AAC score (r=0.608, p=0.041). With multivariate logistic regression analyses, we identified that increased MGP/BMP-2 levels ratio (OR=12.436; 95% CI=1.595-96.971) was an independent predictor in aortic calcification event.

CONCLUSION: We concluded that regulators of calcification including calcification inhibitor and promoter related to oxidative stress, were associated with vascular calcification in CKD. MGP levels were increased in the early of calcification and MGP/BMP-2 levels ratio was a strong predictor for vascular calcification in CKD.

KEYWORDS: vascular calcification, CKD, oxidative stress, 8-isoprostane, MGP, BMP-2

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Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ Res. 2004; 95: 560-7, CrossRef.

Prodjosudjadi W, Suhardjono A. End-stage renal disease in Indonesia: Treatment development. Ethn Dis. 2009; 19 (Suppl 1): S1-33-6, PMID.

Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: Pathobiological mechanisms and clinical implications. Circ Res. 2006; 99: 1044-59, CrossRef.

Csiszar A, Lehoux S, Ungvari Z. Hemodynamic forces, vascular oxidative stress and regulation of BMP-2/4 expression. Antioxid Redox Signal. 2009; 11: 1683-97, CrossRef.

Handelman GJ, Walter MF, Adhikarla R, Gross J, Dallal GE, Levin NW, et al. Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int. 2001; 59: 1960-6, CrossRef.

Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC. Oxidative stress, anti-oxidant therapies and chronic kidney disease. Nephrology. 2012; 17: 311-21, CrossRef.

Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev. 2000; 21: 393-411, CrossRef.

O’Donnell CJ, Shea MK, Price PA, Gagnon DR, Wilson PWF, Larson MG, et al. Matrix gla protein is associated with risk factors for atherosclerosis but not with coronary artery calcification. Arterioscler Thromb Vasc Biol. 2006; 26: 2769-74, CrossRef.

Zebboudj AF, Imura M, Boström K. Matrix gla protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem. 2002; 277: 4388-94, CrossRef.

Honkanen E, Kauppila L, Wikström B, Rensma PL, Krzesinski JM, Aasarod K, et al. Abdominal aortic calcification in dialysis patients: results of the CORD study. Nephrol Dial Transplant. 2008; 23: 4009-15, CrossRef.

Bellasi A, Ferramosca E, Muntner P, Ratti C, Wildman RP, Block GA, et al. Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients. Kidney Int. 2006; 70: 1623-8, CrossRef.

Stompór T. An overview of the pathophysiology of vascular calcification in chronic kidney disease. Perit Dial Int. 2007; 27 (Suppl 2): S215-22, PMID.

Mody N, Parhami F, Safarian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells.Free Radic Biol Med. 2001; 31: 509-19, CrossRef.

Gross M, Steffes M, Jacobs DR Jr, Yu X, Lewis L, Lewis CE, et al. Plasma F2-isoprostanes and coronary artery calcification: The CARDIA study. Clin Chem. 2005; 51: 125-31, CrossRef.

Boström K, Watson KE, Horn S, Wortham C, Herman M, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest. 1993; 91: 1800-9, CrossRef.

Chen NX, Duan D, O’Neill KD, Wolisi GO, Koczman JJ, Laclair R, et al. The mechanisms of uremic serum-induced expression of bone matrix proteins in bovine vascular smooth muscle cells. Kidney Int. 2006; 70: 1046-53, CrossRef.

Thomsen SB, Rathcke CN, Zerahn B, Vestergaard H. Increased levels of the calcification marker Matrix Gla Protein and the inflammatory markers YKL-40 and CRP in patients with type 2 diabetes and ischemic heart disease. Cardiovasc Diabetol. 2010; 9: 86, CrossRef.

Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998; 18: 1400-7, CrossRef.

Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL. Calcification of human vascular cells in vitro is correlated with high levels of matrix gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol. 1998; 18: 379-88, CrossRef.


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