Tropoelastin Inhibits Vascular Calcification via 67-kDa Elastin Binding Protein in Cultured Bovine Aortic Smooth Muscle Cells

Wachi, Hiroshi; Sugitani, Hideki; Murata, Hayato; Nakazawa, Junji; Mecham, Robert P.; Seyama, Yousuke

doi:10.5551/jat.11.159

Cited by 28 publications

(18 citation statements)

References 42 publications

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“…For example, it has been revealed that fibronectin and collagen promote arterial calcification 32) and that elastin, or laminin, inhibits such calcification 33,34) . We have previously reported that elastic fiber-related proteins, TE, fibrillin-1, and Lysyl oxidase, are suppressed by the induction of vascular calcification in cultured BASMCs 12) and the addition of recombinant tropoelastin significantly inhibits arterial calcification via 67 kDa elastin-binding protein (EBP) 15) . It is believed that the hydrophobic sequence of TE, VGVAPG (Val-Gly-Val-Ala-Pro-Gly), binds to EBP 35,36) .…”

Section: Discussionmentioning

confidence: 99%

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Treatment with Vitamin K2 Combined with Bisphosphonates Synergistically Inhibits Calcification in Cultured Smooth Muscle Cells

Saito

Wachi

Sato

et al. 2007

JAT

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Aim: Vascular calcification is a common feature in patients with advanced atherosclerosis, postmenopausal women and patients with renal failure, which results in reduced elasticity of arteries. Pamidronate, a bisphosphonate, is used as a therapeutic agent for anti-osteoporosity, although there are adverse side effects, such as renal damage and aortic inflamed plaque rupture. In the present study, we demonstrated the effects of vitamin K2 alone or in combination with pamidronate in an arterial calcification model induced using inorganic phosphate in cultured bovine aortic smooth muscle cells (BASMCs). Methods: Calcification was induced by the addition of Pi (3 mM) in BASMCs. Calcium deposition was determined by Calcium C-test Wako and von Kossa staining. mRNA expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction. Results: Calcium deposition assay and von Kossa staining showed that calcification could be inhibited in a dose-dependent manner by treatment with vitamin K2 alone, and that its inhibitory effect was enhanced when combined with pamidronate. It was found that the expression of tropoelastin mRNA was synergistically enhanced by combined treatment with vitamin K2 and pamidronate, and the expression matrix Gla protein mRNA and osteopontin mRNA expression were also enhanced and suppressed, respectively, by treatment with vitamin K2 or pamidronate. Moreover, our data showed that the suppression of TE expression by siRNA significantly increased Pi-induced vascular calcification. Conclusion: Taken together, our study suggests that vitamin K2 in combination with pamidronate synergistically inhibits arterial calcification via the increased expression of tropoelastin, which would be a useful marker for developing effective therapeutic or prophylactic agents for arterial calcification.

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Section: Discussionmentioning

confidence: 99%

“…In vitro calcification was induced as described previously [13][14][15][16] , with slight modifications. Briefly, confluent cells were incubated in DMEM containing 4.5 g/L glucose supplemented with 10% FBS in the presence of Pi (3 mM).…”

Section: Cell Culture and Induction Of In Vitro Calcificationmentioning

confidence: 99%

Treatment with Vitamin K2 Combined with Bisphosphonates Synergistically Inhibits Calcification in Cultured Smooth Muscle Cells

Saito

Wachi

Sato

et al. 2007

JAT

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“…In calcified aorta or uremic rats, mRNA levels of Pit-1 and Cbfa-1 have been shown to increase, supporting the evidence that Pit-1 modulates osteoblastic differentiation of VSMCs 15) . Seyama et al 16) demonstrated that elastin is a critical protein that regulates the phenotypic modulation of VSMCs and its expression is reduced during Pi-induced calcification 17) . This observation suggests an association of the extracellular matrix with the calcification in VSMCs.…”

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confidence: 99%

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

Son

Akishita

Iijima

et al. 2008

JAT

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Vascular calcification is clinically important in the development of cardiovascular disease. It has been suggested that apoptosis is one of the processes regulating calcification in vascular smooth muscle cells (VSMC). In this review, we discuss the role of apoptosis in inorganic phosphate (Pi)-induced calcification, focusing on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6). Further, we mention the beneficial effect of statins mediated by inhibition of apoptosis which is accompanied by restoration of the Gas6-mediated survival pathway. These findings indicate that Gas6 is a novel target of statins' effects to prevent vascular calcification.

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“…Pi-induced calcification was partially suppressed after the addition of tropoelastin, due to elastic fiber formation. Therefore, tropoelastin and elastic fibers may contribute to the inhibition of vascular calcification via the 67-kDa elastin binding protein on the cell surface (43,44). In addition to similar phenomena in endothelin-1, we demonstrated the expression of tropoelastin and lysyl oxidase at the gene level, as induced by endothelin-1, in cultured SMCs.…”

Section: Aortic Calcificationmentioning

confidence: 56%

Atherosclerosis and Matrix Dystrophy

Seyama

Wachi

2004

JAT

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Atherosclerosis is characterized by inflammatory metabolic change with lipid accumulation in the artery. Atherosclerotic plaque occurs at discrete locations in the arterial system and involves the proliferation of smooth muscle cells (SMCs) together with imbalance of the extracellular matrix elements, elastic fiber in particular. The role of elastin in arterial development and disease was confirmed by generating mice that lack elastin. Thus, elastin is a critical regulatory molecule that regulates the phenotypic modulation, proliferation and migration of SMCs. We estimated that elastin expression and SMC proliferation are coupled inversely: potent stimulators of cell proliferation may potentially inhibit elastin expression and potent inhibitors of cell proliferation can stimulate elastin expression. Moreover, elastin was found to be expressed maximally at the G0 and minimally at the G2/M phase during the cell cycle, suggesting that its expression is regulated by the cell growth state. The elastin peptide VPGVG enhanced SMC proliferation, resulting in the reduction of elastin expression. The inhibition of elastin expression by elastin fragments may be reflected in the negative feedback regulatory mechanism. The relationship between cell proliferation and elastin expression may be changed in atherosclerosis. Areas of atherosclerotic plaque show abnormality of elasticity and permeability from the viewpoint of the physiological function of the arterial wall. The etiology was estimated to be that cholesterol and calcium are deposited on the elastic fiber, resulting in decreased elastin synthesis and crosslinking formation. In addition, these dysfunctions of elastin fiber are also associated, in that the down-regulation of elastin and its related components (fibrillin-1 and lysyl oxidase) are directly related to calcification in SMCs. The denatured arterial elastin by cholesterol and calcium accumulation was also susceptible to proteolytic enzymes such as elastase and matrix metalloproteinase (MMP). Therefore, metabolic change in elastic fiber induces decreased elasticity and is associated with essential hypertension. Vitamin K2 is used in drug therapy against atherosclerosis, or calcification in diabetes mellitus or dialysis, due to its promotion of the carboxylation of the matrix Gla protein. The heart and arteries are always active mechanically and seem to wear out more than any other system or organs. The potential energy accumulated in the stretching of the vessel wall during contraction of the heart (systole) is dissipated in the elastic recoil of the wall during the period when the heart is inactive (diastole). This release of tension in the wall serves as an auxiliary pump, forcing the blood forward during diastole. Thus, near the heart, the flow of blood is intermittent and it is associated with the elasticity of the wall. The walls of the large conducting vessels make it possible to have a continuous flow with an intermittent pump. The normal human artery wall comprises endothelial cells with a few under-

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Tropoelastin Inhibits Vascular Calcification via 67-kDa Elastin Binding Protein in Cultured Bovine Aortic Smooth Muscle Cells

Cited by 28 publications

References 42 publications

Treatment with Vitamin K2 Combined with Bisphosphonates Synergistically Inhibits Calcification in Cultured Smooth Muscle Cells

Treatment with Vitamin K2 Combined with Bisphosphonates Synergistically Inhibits Calcification in Cultured Smooth Muscle Cells

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

Atherosclerosis and Matrix Dystrophy

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