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. Background: Extracellular matrix protein PCPE2 is linked to alterations in HDL size and concentration. Results: PCPE2 protects against diet-induced atherosclerosis by promoting HDL catabolism, reverse cholesterol transport, and SR-BI-mediated uptake of HDL-cholesteryl ester. Conclusion: PCPE2 mediates HDL function by reducing lipid and immune cell accumulation in the artery. Significance: These findings establish a role for the extracellular matrix glycoprotein PCPE2 in SR-BI-mediated HDL function and the prevention of atherosclerosis.