Abstract
Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.
Highlights
Vascular calcification is caused by abnormal deposition of calcium phosphate crystals in the blood vessels and is linked to cardiovascular morbidity and mortality in patients with metabolic syndrome, chronic renal failure, or atherosclerosis
By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. We found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the mouse double minute 2 homolog (MDM2) promoter region, which resulted in transcriptional activation of MDM2
Exogenous Msx[1] or Msx[2] potentiated Piinduced calcium deposition. These enhancing effects were blocked by transfection of Mdm[2] siRNA (Fig. 5e). These results suggest that both MSX1 and msh homeobox 2 (MSX2) can induce calcium deposition by upregulating MDM2, which is followed by downregulation of HDAC1 and derepression of RUNX2
Summary
Vascular calcification is caused by abnormal deposition of calcium phosphate crystals in the blood vessels and is linked to cardiovascular morbidity and mortality in patients with metabolic syndrome, chronic renal failure, or atherosclerosis. Vascular calcification often coexists with other metabolic or cardiovascular diseases, it is currently considered an independent disease process[1]. Because vascular calcification often results in adverse hemodynamic events owing to reduced blood vessel elasticity and causes increased pulse pressure and systolic hypertension[2], it is a target for active intervention. Vascular calcification involves many osteoblast-like cells and intermediates[3,4]. Pericytes[7], adventitial myofibroblasts[8,9], and vascular progenitor cells[10] may be cellular sources of osteoblast-like cells in the development of vascular calcification
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