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

Overview

Journal Sci Rep

Specialty Science

Date 2015 Nov 13

PMID 26560812

Citations 43

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

Affiliations

Soon will be listed here.

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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