PAQR3 depletion accelerates diabetic wound healing by promoting angiogenesis through inhibiting STUB1-mediated PPARγ degradation

The pathogenesis of diabetic wounds is closely associated with the dysregulation of macrophage polarization. However, the underlying mechanism remains poorly understood. In this study, we aimed to investigate the potential effects of PAQR3 (progestin and adipoQ receptor 3) silencing in accelerating diabetic wound healing. We showed that PAQR3 silencing promoted skin wound healing and angiogenesis in diabetic mice, which was accompanied by enhanced M2 macrophage polarization and elevated expression of PPAR gamma (peroxisome proliferator-activated receptor gamma). PAQR3 silencing also promoted M2 polarization and increased PPAR gamma protein level in PMA-treated THP-1 cells. Moreover, knockdown of PAQR3 in macrophages enhanced the migration of HaCaT cells and tube formation of HUVECs. The ubiquitination of PPAR gamma protein in macrophages was repressed by PAQR3 silencing. STUB1 (STIP1 homology and U-box-containing protein 1) binds with the PPAR gamma protein to mediate PPAR gamma ubiquitination and degradation in macrophages, which was impaired by PAQR3 silencing. The PPAR gamma inhibitor, GW9662, or STUB1 overexpression abrogated the enhanced M2 macrophage polarization induced by PAQR3 silencing. Therefore, these findings demonstrates that PAQR3 silencing accelerates diabetic wound healing by promoting M2 macrophage polarization and angiogenesis, which is mediated by the inhibition of STUB1-mediated PPAR gamma protein ubiquitination and degradation. PAQR3 silencing promotes skin wound healing and angiogenesis, enhanced macrophage M2 polarization and elevated expression of PPAR gamma in diabetic mice. PAQR3 silencing in macrophages also enhances migration of HaCaT cells and tube formation of HUVECs in vitro. The promotion of diabetic wound healing through M2 macrophage polarization and angiogenesis by PAQR3 silencing is mediated by the inhibition of STUB1-mediated PPAR gamma protein ubiquitination and degradation.

Automated summary

PAQR3 silencing accelerates diabetic wound healing by promoting M2 macrophage polarization and angiogenesis, which is mediated by the inhibition of STUB1-mediated PPAR gamma protein ubiquitination and degradation.