Expression of REG? in atherosclerotic plaques and promotes endothelial cells apoptosis via the cyclophilin A pathway indicates functional implications in atherogenesis.

ABSTRACT: REG? is a member of the 11S regulatory particles family of proteasome activators and has been shown to promote the degradation of intact cellular proteins in a ubiquitin- and ATP-independent manner in the progression of various diseases. Our previous studies showed that REG?-proteasome promotes Protein kinase A catalytic subunit ? (PKAc?) turnover to modulate Forkhead box protein O1 (FoxO1) cellular activity in vascular endothelial cell migration and angiogenesis. We, therefore, studied the expression and novel functional implications and pathways involving REG? in atherogenesis. We studied the expression of REG? in atherosclerotic plaques in the ApoE-/- mouse model. Using immunohistochemistry, we showed that REG? was highly expressed in these plaques, and the result of RNA-seq in Human umbilical vein endothelial cells (HUVECs), led us to explore and indentify that REG? significantly promoted cyclophilin A (CyPA) expression, which is a proinflammatory and proapoptotic molecule in atherosclerosis progression. Next, we studied the regulation of REG? in CyPA expression, and the proapoptotic effect on Endothelial cells (ECs). REG? promoted CyPA expression via the REG?-PKA-FoxO1-CyPA axis, and stimulated CyPA-dependent ECs apoptosis in vitro. Our data indicated that REG? had proapoptotic effects on ECs depends on CyPA pathway in vitro and functional implications in atherogenesis in vivo.

SUBMITTER: Xie Y 

PROVIDER: S-EPMC6681779 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature