J Korean Med Sci.  2017 Nov;32(11):1738-1748. 10.3346/jkms.2017.32.11.1738.

New Aspects of Vascular Calcification: Histone Deacetylases and Beyond

• Kwon DH
• Kim YK
• Kook H

• KMID: 2390298
• DOI: http://doi.org/10.3346/jkms.2017.32.11.1738

Abstract

Vascular calcification is a pathologic phenomenon in which calcium phosphate is ectopically deposited in the arteries. Previously, calcification was considered to be a passive process in response to metabolic diseases, vascular or valvular diseases, or even aging. However, now calcification is recognized as a highly-regulated consequence, like bone formation, and many clinical trials have been carried out to elucidate the correlation between vascular calcification and cardiovascular events and mortality. As a result, vascular calcification has been implicated as an independent risk factor in cardiovascular diseases. Many molecules are now known to be actively associated with this process. Recently, our laboratory found that posttranslational modification of histone deacetylase (HDAC) 1 is actively involved in the development of vascular calcification. In addition, we found that modulation of the activity of HDAC as well as its protein stability by MDM2, an HDAC1-E3 ligase, may be a therapeutic target in vascular calcification. In the present review, we overview the pathomechanism of vascular calcification and the involvement of posttranslational modification of epigenetic regulators.

Keyword

Vascular Calcification; Histone Deacetylase; MDM2; Posttranslational Modification

MeSH Terms

Aging
Arteries
Calcium
Cardiovascular Diseases
Epigenomics
Histone Deacetylases*
Histones*
Metabolic Diseases
Mortality
Osteogenesis
Protein Processing, Post-Translational
Protein Stability
Risk Factors
Vascular Calcification*
Calcium
Histone Deacetylases
Histones

Figure

• 

  Fig. 1 Class, molecular structure, numbers of amino acids, estimated molecular weights, and tissue distribution of the HDACs. The key to the colored box is as follows: black, HDAC domain; red, MEF2C binding domain; yellow, nuclear localization signal; blue, nuclear export signal. Molecular weights of HDACs on western blot gels are higher than expected owing to their posttranslational modifications. To simplify the diagram, the detailed structure of the class III HDAC with NAD+-dependent deacetylase activity is not shown. HDAC = histone deacetylase, MEF2C = myocyte enhancer factor 2C.

• 

  Fig. 2 Diagram of the working mechanism of HDAC1 and MDM2, an HDAC1-E3 ligase, in the development of vascular calcification. In the healthy condition, HDAC1 inhibits osteogenic gene expression including that of RUNX2 in VSMCs. With calcification stresses, MDM2 expression is increased in VSMCs, resulting in the polyubiquitination-dependent proteasomal degradation of HDAC1. The reduced HDAC1 protein amount then causes the de-repression of calcifying genes, followed by an increase in calcium deposition in VSMCs. Therapeutic use of HDAC inhibitors in various diseases may inhibit the deacetylase activity of HDAC1, thus causing unwanted vascular calcification. In contrast, either treatment with RG 7112, an MDM2 inhibitor, or interruption of the polyubiquitination of HDAC1 may be beneficial in preventing vascular calcification (78). HDAC = histone deacetylase, RUNX2 = runt-related transcription factor 2, VSMC = vascular smooth muscle cell.

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