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

Abstract

ABSTRACTREGγ 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 REGγ-proteasome promotes Protein kinase A catalytic subunit α (PKAcα) 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 REGγ in atherogenesis. We studied the expression of REGγ in atherosclerotic plaques in the ApoE-/- mouse model. Using immunohistochemistry, we showed that REGγ 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 REGγ significantly promoted cyclophilin A (CyPA) expression, which is a proinflammatory and proapoptotic molecule in atherosclerosis progression. Next, we studied the regulation of REGγ in CyPA expression, and the proapoptotic effect on Endothelial cells (ECs). REGγ promoted CyPA expression via the REGγ-PKA-FoxO1-CyPA axis, and stimulated CyPA-dependent ECs apoptosis in vitro. Our data indicated that REGγ had proapoptotic effects on ECs depends on CyPA pathway in vitro and functional implications in atherogenesis in vivo.