title: 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.
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.
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Ricquita D
authors.initials: RD
authors.lastname: Pollard
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06268.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Blesso
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Manal
authors.initials: M
authors.lastname: Zabalawi
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Brian
authors.initials: B
authors.lastname: Fulp
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Mark
authors.initials: M
authors.lastname: Gerelus
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
authors.forename: Erica W
authors.initials: EW
authors.lastname: Lyons
authors.affiliation: Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Nebil
authors.initials: N
authors.lastname: Nuradin
authors.affiliation: Shire Human Genetic Therapies, Lexington, Massachusetts 02421.
authors.forename: Omar L
authors.initials: OL
authors.lastname: Francone
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, Kentucky 40506.
authors.forename: Xiang-An
authors.initials: XA
authors.lastname: Li
authors.affiliation: Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Daisy
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: msthomas@mcw.edu.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D001693:Biological Transport, Active / Q000235:genetics; D016466:CHO Cells; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D003412:Cricetulus; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D011973:Receptors, LDL; D051122:Scavenger Receptors, Class B; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C059714:HDL cholesteryl ester; C491552:Pcolce2 protein, mouse; C454739:Scarb1 protein, mouse
keywords: apolipoprotein; atherosclerosis; cholesterol metabolism; extracellular matrix protein; high-density lipoprotein (HDL); scavenger receptor