Abstract
Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.
Highlights
Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases
Under conditions that lead to calcification, the expression of MDM2 is induced, and MDM2 acts as an E3 ligase to ubiquitinate histone deacetylase 1 (HDAC1)
The reduction of HDAC1 contributes to the potentiation of VC, which is somewhat coincident with our result that HDACi exaggerates VC
Summary
Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. We report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC. Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea. Department of Pharmacology, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea. We report that proteasome-dependent degradation of HDAC1 results in the enhancement of VC, and that MDM2 acts as an E3 ubiquitin ligase of HDAC1 in response to calcification stimuli
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