title: Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation.
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.
authors.affiliation: Department of Biomedical Science, Graduate School of Medicine, Kyungpook National University.
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Kyungpook National University.|Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Gumi, Republic of Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Kyungpook National University.
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kyungpook National University.|GIST College, Gwangju Institute of Science and Technology.
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University.|Research Institute of Clinical Medicine, Chonnam National University Hwasun Hospital, Gwangju, Republic of Korea.
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation.
authors.forename: Nam
authors.initials: N
authors.lastname: Doo Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Do
authors.affiliation: Department of Internal Medicine, Kyungpook National University.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Go
authors.forename: Chae-Myeong
authors.initials: CM
authors.lastname: Ha
authors.affiliation: Department of Internal Medicine, Kyungpook National University.
authors.forename: Chae-Myung
authors.initials: CM
authors.lastname: Ha
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University.|BK21 plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Surgery, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Seung
authors.initials: S
authors.lastname: Huh
authors.affiliation: Department of Fundamental Medical and Pharmaceutical Sciences, Catholic University of Daegu, Gyeongsan, Republic of Korea.
authors.forename: Nam
authors.initials: N
authors.lastname: Ho Jeoung
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Kyungpook National University.|Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Roudebush VA Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine, Kyungpook National University.|Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University.|BK21 plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D016723:Bone Remodeling / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D051904:Smad8 Protein / Q000378:metabolism*; D061205:Vascular Calcification / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4