Procollagen C-endopeptidase enhancer protein 2 (PCPE2) reduces atherosclerosis in mice by enhancing scavenger receptor class B1 (SR-BI)-mediated high-density lipoprotein (HDL)-cholesteryl ester uptake

Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr^-/-, PCPE2^-/- mice, which had elevated HDL levels compared with 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 with LDLr^-/- mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system.