Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice

Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Kei Yunoki, Yasushi Koyama, Minoru Satoh, Megumi Kondo, Kazuhiro Osawa, Omer F. Hatipoglu, Toru Miyoshi, Masashi Yoshida, Hiroshi Morita, Hiroshi Itoh

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Abstract

Background: The klotho gene was identified as an “aging-suppressor” gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. Methods and results: Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. Conclusions: EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

Original languageEnglish
Article numbere0181009
JournalPLoS One
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

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Eicosapentaenoic Acid
calcification
eicosapentaenoic acid
mutants
mice
Food
NADPH Oxidase
Genes
Gene expression
smooth muscle
myocytes
Smooth Muscle Myocytes
food safety
Muscle
Omega-3 Fatty Acids
Gene Expression
omega-3 fatty acids
gene expression
suppressor genes
Suppressor Genes

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice. / Nakamura, Kazufumi; Miura, Daiji; Saito, Yukihiro; Yunoki, Kei; Koyama, Yasushi; Satoh, Minoru; Kondo, Megumi; Osawa, Kazuhiro; Hatipoglu, Omer F.; Miyoshi, Toru; Yoshida, Masashi; Morita, Hiroshi; Itoh, Hiroshi.

In: PLoS One, Vol. 12, No. 8, e0181009, 01.08.2017.

Research output: Contribution to journalArticle

Nakamura, K, Miura, D, Saito, Y, Yunoki, K, Koyama, Y, Satoh, M, Kondo, M, Osawa, K, Hatipoglu, OF, Miyoshi, T, Yoshida, M, Morita, H & Itoh, H 2017, 'Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice', PLoS One, vol. 12, no. 8, e0181009. https://doi.org/10.1371/journal.pone.0181009
Nakamura, Kazufumi ; Miura, Daiji ; Saito, Yukihiro ; Yunoki, Kei ; Koyama, Yasushi ; Satoh, Minoru ; Kondo, Megumi ; Osawa, Kazuhiro ; Hatipoglu, Omer F. ; Miyoshi, Toru ; Yoshida, Masashi ; Morita, Hiroshi ; Itoh, Hiroshi. / Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice. In: PLoS One. 2017 ; Vol. 12, No. 8.
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abstract = "Background: The klotho gene was identified as an “aging-suppressor” gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. Methods and results: Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5{\%} EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. Conclusions: EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.",
author = "Kazufumi Nakamura and Daiji Miura and Yukihiro Saito and Kei Yunoki and Yasushi Koyama and Minoru Satoh and Megumi Kondo and Kazuhiro Osawa and Hatipoglu, {Omer F.} and Toru Miyoshi and Masashi Yoshida and Hiroshi Morita and Hiroshi Itoh",
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AU - Miura, Daiji

AU - Saito, Yukihiro

AU - Yunoki, Kei

AU - Koyama, Yasushi

AU - Satoh, Minoru

AU - Kondo, Megumi

AU - Osawa, Kazuhiro

AU - Hatipoglu, Omer F.

AU - Miyoshi, Toru

AU - Yoshida, Masashi

AU - Morita, Hiroshi

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N2 - Background: The klotho gene was identified as an “aging-suppressor” gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. Methods and results: Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. Conclusions: EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

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