Abstract
Vascular calcification (VC) often associates with many cardiovascular and metabolic diseases. Although VC is the cause of high morbidity and mortality, molecular mechanisms have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity enhanced VC in vivo and in vitro . HDAC1 protein was reduced in cell and animal calcification models and in human calcified coronary artery and this reduction preceded VC. Calcification stresses induced MDM2 E3 ligase, which resulted in HDAC1 K74 ubiquitination. Forced expression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. A decoy peptide spanning HDAC1 K74 prevented VC. These results demonstrate a previously unknown ubiquitination pathway as well as the involvement of HDAC1 in VC. Our results suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.
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