PDZ domain containing protein 1 aggravates mouse vascular smooth muscle cells calcification via PDZ1 domain mediated β-catenin stabilization and nuclear translocation

Vascular calcification is tightly associated with cardiometabolic risk events. PDZK1 (PDZ domain containing 1) has been implicated in protecting from atherosclerosis, however, its relationship with vascular calcification remains unclear. Here we show that the expression levels of PDZK1 are notably boosted in calcified mice aortas, human and mouse vascular smooth muscle cells (VSMCs). PDZK1 deficiency in mice improves aortic calcification mediated by excessive vitamin D3 (VitD3). Consistently, blocking PDZK1 in human and mouse VSMCs effectively alleviates vascular calcification caused by high phosphate (Pi). PDZK1 overexpression in vitro promotes vascular calcification. Mechanistically, PDZK1 positively regulates the expression of β-catenin and its phosphorylated form at serine 552 (p-β-catenin^Ser552). Rescue experiments confirm that β-catenin is a critical mediator through which PDZK1 exacerbates vascular calcification. PDZK1 extends the half-life of β-catenin and p-β-catenin^Ser552 by blocking their ubiquitination and degradation. Furthermore, inhibition of PDZK1 attenuates high Pi-induced nuclear translocation of β-catenin whereas PDZK1 overexpression facilitates this process. More deeply, we reveal the direct interaction between PDZK1 and β-catenin is mediated by binding of β-catenin to the PDZ1 domain of PDZK1. These findings elucidate a novel PDZK1/β-catenin axis in vascular calcification progression and provide a potential therapeutic target for treating cardiovascular calcification in high-risk populations.