Endocrinol Metab.  2016 Mar;31(1):52-61. 10.3803/EnM.2016.31.1.52.

Mechanisms of Vascular Calcification: The Pivotal Role of Pyruvate Dehydrogenase Kinase 4

• Leem J
• Lee IK

• KMID: 2169692
• DOI: http://doi.org/10.3803/EnM.2016.31.1.52

Abstract

Vascular calcification, abnormal mineralization of the vessel wall, is frequently associated with aging, atherosclerosis, diabetes mellitus, and chronic kidney disease. Vascular calcification is a key risk factor for many adverse clinical outcomes, including ischemic cardiac events and subsequent cardiovascular mortality. Vascular calcification was long considered to be a passive degenerative process, but it is now recognized as an active and highly regulated process similar to bone formation. However, despite numerous studies on the pathogenesis of vascular calcification, the mechanisms driving this process remain poorly understood. Pyruvate dehydrogenase kinases (PDKs) play an important role in the regulation of cellular metabolism and mitochondrial function. Recent studies show that PDK4 is an attractive therapeutic target for the treatment of various metabolic diseases. In this review, we summarize our current knowledge regarding the mechanisms of vascular calcification and describe the role of PDK4 in the osteogenic differentiation of vascular smooth muscle cells and development of vascular calcification. Further studies aimed at understanding the molecular mechanisms of vascular calcification will be critical for the development of novel therapeutic strategies.

Keyword

Vascular calcification; Vascular smooth muscle cells; Pyruvate dehydrogenase kinase 4; Bone morphogenetic proteins; Osteogenic differentiation; Mitochondria

MeSH Terms

Aging
Atherosclerosis
Bone Morphogenetic Proteins
Diabetes Mellitus
Metabolic Diseases
Metabolism
Mitochondria
Mortality
Muscle, Smooth, Vascular
Osteogenesis
Oxidoreductases*
Phosphotransferases*
Pyruvic Acid*
Renal Insufficiency, Chronic
Risk Factors
Vascular Calcification*
Bone Morphogenetic Proteins
Oxidoreductases
Phosphotransferases
Pyruvic Acid

Figure

• 

  Fig. 1 The regulatory action of pyruvate dehydrogenase kinase 4 (PDK4) on the signaling pathway downstream of bone morphogenetic protein 2 (BMP2) during vascular calcification. Under calcifying conditions, BMP2 binds to type I and II receptors and triggers formation of a heteromeric complex. After activation by the type II receptors, the type I receptors phosphorylate small mothers against decapentaplegic (SMAD) 1/5/8 to propagate the signal into the cell. SMAD1/5/8 form heteromeric complexes with SMAD4 and move into the nucleus, where they assemble into transcriptional machinery that regulates the expression of osteogenic genes. Under normal conditions, PDK4 is located in the mitochondrial matrix. However, under calcifying conditions, PDK4 may be transported into the cytosol and activate SMAD1/5/8 by direct phosphorylation, leading to the translocation of phosphorylated SMADs into the nucleus for transcriptional regulation of osteogenic genes, thus enhancing BMP2 signaling pathway activity.

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