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.

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Published in The Journal of Biological Chemistry, v. 290, no. 25, p. 15496-15511.

This research was originally published in The Journal of Biological Chemistry. Ricquita D. Pollard, Christopher N. Blesso, Manal Zabalawi, Brian Fulp, Mark Gerelus, Xuewei Zhu, Erica W. Lyons, Nebil Nuradin, Omar L. Francone, Xiang-An Li, Daisy Sahoo, Michael J. Thomas, and Mary G. Sorci-Thomas. 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. The Journal of Biological Chemistry. 2015; 290:15496-15511. © the American Society for Biochemistry and Molecular Biology.

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This work was supported, in whole or in part, by National Institutes of Health Grants NHLBI HL-112270, HL 112276, and HL 127649 (to M. G. S.-T.). This work was also supported by American Heart Association Grants 09GRNT2280053 and 14GRNT20500029 (to M. J. T.). The authors declare that they have no conflicts of interest with the contents of this article.

Ricquita D. Pollard is supported by National Institutes of Health Diversity Supplement Grant HL112270A1S1.

Christoper N. Blesso is supported by post-doctoral American Heart Association Grant 13POST17000005.

Daisy Sahoo is supported by National Institutes of Health Grant RO1-HL058012.

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