Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases remain unclear. Here, researchers report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity by chemical inhibitors or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cellular and animal calcification models and in human calcified coronary arteries. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC, mediated by the MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. MDM2 overexpression enhances VC, whereas MDM2 depletion attenuates VC. A decoy peptide spanning HDAC1 K74 and the MDM2 inhibitor RG 7112 inhibit VC in vitro and in vivo. These results reveal a previously unappreciated ubiquitination pathway and suggest that MDM2-mediated HDAC1 ubiquitination is a novel therapeutic target for VC.
The researchers investigated whether MDM2 could induce VC. MDM2 adenovirus (Ad-MDM2) infection induced calcium deposition in RVSMCs only at higher doses (the fourth column in Figure 1a). However, under Pi treatment, Ad-MDM2 significantly enhanced calcium deposition in RVSMCs in a dose-dependent manner (the fifth to eighth columns in Figure 1a). In addition, MDM2 siRNA significantly attenuated Pi-induced calcium deposition in A10 cells (Figure 1b).
Figure 1. (a) Adenoviral infection of MDM2 enhanced Pi-induced VC in a dose-dependent manner. (b) MDM2 siRNA blunted Pi-induced VC in A10 cells. (Kwon D H, et al., 2016)
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