Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

Sun Joo Lee, Ji Yun Jeong, Chang Joo Oh, Sungmi Park, Joon Young Kim, Han Jong Kim, Nam Doo Kim, Young Keun Choi, Ji Yeon Do, Younghoon Go, Chae Myung Ha, Je Yong Choi, Seung Huh, Nam Ho Jeoung, Ki Up Lee, Hueng Sik Choi, Yu Wang, Keun Gyu Park, Robert Harris, In Kyu Lee

Research output: Contribution to journalArticle

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Abstract

Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.

Original languageEnglish (US)
Article number16577
JournalScientific Reports
Volume5
DOIs
StatePublished - Nov 12 2015

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Vascular Calcification
Phosphorylation
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phosphates
Pyruvate Dehydrogenase Complex
Cholecalciferol
pyruvate dehydrogenase kinase 4
Osteogenesis
Atherosclerosis
Homeostasis
Up-Regulation
Pharmacology
Apoptosis
Morbidity
Mortality

ASJC Scopus subject areas

  • General

Cite this

Lee, S. J., Jeong, J. Y., Oh, C. J., Park, S., Kim, J. Y., Kim, H. J., ... Lee, I. K. (2015). Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation. Scientific Reports, 5, [16577]. https://doi.org/10.1038/srep16577

Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation. / Lee, Sun Joo; Jeong, Ji Yun; Oh, Chang Joo; Park, Sungmi; Kim, Joon Young; Kim, Han Jong; Doo Kim, Nam; Choi, Young Keun; Do, Ji Yeon; Go, Younghoon; Ha, Chae Myung; Choi, Je Yong; Huh, Seung; Ho Jeoung, Nam; Lee, Ki Up; Choi, Hueng Sik; Wang, Yu; Park, Keun Gyu; Harris, Robert; Lee, In Kyu.

In: Scientific Reports, Vol. 5, 16577, 12.11.2015.

Research output: Contribution to journalArticle

Lee, SJ, Jeong, JY, Oh, CJ, Park, S, Kim, JY, Kim, HJ, Doo Kim, N, Choi, YK, Do, JY, Go, Y, Ha, CM, Choi, JY, Huh, S, Ho Jeoung, N, Lee, KU, Choi, HS, Wang, Y, Park, KG, Harris, R & Lee, IK 2015, 'Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation', Scientific Reports, vol. 5, 16577. https://doi.org/10.1038/srep16577
Lee, Sun Joo ; Jeong, Ji Yun ; Oh, Chang Joo ; Park, Sungmi ; Kim, Joon Young ; Kim, Han Jong ; Doo Kim, Nam ; Choi, Young Keun ; Do, Ji Yeon ; Go, Younghoon ; Ha, Chae Myung ; Choi, Je Yong ; Huh, Seung ; Ho Jeoung, Nam ; Lee, Ki Up ; Choi, Hueng Sik ; Wang, Yu ; Park, Keun Gyu ; Harris, Robert ; Lee, In Kyu. / Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation. In: Scientific Reports. 2015 ; Vol. 5.
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abstract = "Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.",
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AU - Kim, Joon Young

AU - Kim, Han Jong

AU - Doo Kim, Nam

AU - Choi, Young Keun

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AU - Huh, Seung

AU - Ho Jeoung, Nam

AU - Lee, Ki Up

AU - Choi, Hueng Sik

AU - Wang, Yu

AU - Park, Keun Gyu

AU - Harris, Robert

AU - Lee, In Kyu

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AB - Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.

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