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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.
Highlights
Vascular medial calcification is prevalent in patients with diabetes, chronic renal failure (CRF), and in aging
Since we find that pyruvate dehydrogenase kinase 4 (PDK4) is the only Pyruvate dehydrogenase kinase (PDK) that increases under conditions that promote calcification, these findings suggest PDK4 is upregulated by conditions that promote upregulation of osteogenic gene markers and calcification in human vessels and vascular smooth muscle cells (VSMCs)
This study provides the first evidence that PDK4 plays an important role in osteogenic switching in VSMCs by direct phosphorylation of SMAD1/5/8 under calcifying conditions
Summary
Vascular medial calcification is prevalent in patients with diabetes, chronic renal failure (CRF), and in aging. Under conditions that promote calcification such as high Pi, or toxic levels of vitamin D, extra PDK4 activity might play a role in regulating osteogenic gene expression, in which it promotes vascular calcification by directly phosphorylating SMAD1/5/8, in addition to inducing mitochondrial dysfunction followed by apoptosis. These findings delineate a novel role for PDK4 in vascular calcification and suggest that this enzyme is a promising drug target for the treatment of patients with vascular calcification
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