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: 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-Myeong Ha, Chae-Myung Ha, Je-Yong Choi, Seung Huh, Nam Ho Jeoung, Ki-Up Lee, Hueng-Sik Choi, Yu Wang, Keun-Gyu Park, Robert A Harris, In-Kyu Lee
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 16577 (Nov 12 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26560812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Protein Kinase Inhibitors
• Smad1 Protein
• Smad5 Protein
• Smad8 Protein
• Protein Kinases
• pyruvate dehydrogenase kinase 4

Topics

• Animals
• Apoptosis (genetics)
• Biomarkers
• Bone Remodeling (genetics)
• Cell Differentiation
• Cells, Cultured
• Disease Models, Animal
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Male
• Mice
• Mice, Knockout
• Mitochondria (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, metabolism)
• Myocytes, Smooth Muscle (cytology, metabolism)
• Osteogenesis (genetics)
• Phosphorylation
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (chemistry, genetics, metabolism)
• Smad1 Protein (metabolism)
• Smad5 Protein (metabolism)
• Smad8 Protein (metabolism)
• Vascular Calcification (metabolism)