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. J Biol Chem 2015 Jun 19;290(25):15496-15511
Date
05/08/2015Pubmed ID
25947382Pubmed Central ID
PMC4505464DOI
10.1074/jbc.M115.646240Scopus ID
2-s2.0-84939623747 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
Author List
Pollard RD, Blesso CN, Zabalawi M, Fulp B, Gerelus M, Zhu X, Lyons EW, Nuradin N, Francone OL, Li XA, Sahoo D, Thomas MJ, Sorci-Thomas MGAuthors
Daisy Sahoo PhD Dean, Professor in the Medicine department at Medical College of WisconsinMary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntigens, CD
Antigens, Differentiation, Myelomonocytic
Aorta
Apolipoprotein A-I
Atherosclerosis
Biological Transport, Active
CHO Cells
Cholesterol Esters
Cricetulus
Glycoproteins
Humans
Intracellular Signaling Peptides and Proteins
Lipoproteins, HDL
Macrophages
Mice
Mice, Knockout
Receptors, LDL
Scavenger Receptors, Class B