PCPE2 modulates HDL and SR-BI function in atherosclerosis

Studies in human populations have shown a significant correlation between procollagen cendopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2 is a 52 kDa glycoprotein located in the extracellular matrix and enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice and determining if they protected against dietinduced atherosclerosis. PCPE2 deficient mice were crossed with LDL receptor deficient mice to obtain LDLr-/-, PCPE2-/- mice, which had elevated HDL levels compared to LDLr-/- mice with similar LDL concentrations. We found that LDLr-/-, PCPE2-/- mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr-/- mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr-/-, PCPE2-/- mice was similar to that reported for LDLr-/-, apoA-I-/- mice, which lack any apoA-I/HDL. Furthermore, LDLr-/-, PCPE2-/- mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared to LDLr-/- mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SRBI function by increasing the rate of HDL cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is athero-protective and it is an important component of the reverse cholesterol transport HDL system.