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J Biol Chem. 2015 Jun 19;290(25):15496-511. doi: 10.1074/jbc.M115.646240. Epub 2015 May 6.

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.

Author information

1
the Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
2
the Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06268.
3
From the Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
4
Shire Human Genetic Therapies, Lexington, Massachusetts 02421, and.
5
the Department of Pediatrics, University of Kentucky, Lexington, Kentucky 40506.
6
From the Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, msthomas@mcw.edu.

Abstract

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.

KEYWORDS:

apolipoprotein; atherosclerosis; cholesterol metabolism; extracellular matrix protein; high-density lipoprotein (HDL); scavenger receptor

PMID:
25947382
PMCID:
PMC4505464
DOI:
10.1074/jbc.M115.646240
[Indexed for MEDLINE]
Free PMC Article

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