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

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