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Daisy Sahoo - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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 is a 52 kDa glycoProtein located in the extracellular matrix and enhances the cleavage of C-terminal procollagen by bone morphogenetic Protein 1 (BMP1). Our studies focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice and determining if 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 to 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 to 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 cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is athero-protective and it is an important component of the reverse cholesterol transport HDL system.
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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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.
Ricquita D Pollard - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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 is a 52 kDa glycoProtein located in the extracellular matrix and enhances the cleavage of C-terminal procollagen by bone morphogenetic Protein 1 (BMP1). Our studies focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice and determining if 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 to 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 to 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 cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is athero-protective and it is an important component of the reverse cholesterol transport HDL system.
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abstract 671 beyond cholesterol efflux defining hdl function in atherosclerosis and the requirement for procollagen c endopeptidase Enhancer Protein 2
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Ricquita D Pollard, Michael J Thomas, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mary G SorcithomasAbstract:Recent studies suggest that assessment of high density lipoProtein (HDL) function provides a more reliable metric of athero-protection than plasma concentration alone. One important function attributed to apolipoProtein A-I (apoA-I), the major Protein constituent of HDL, is its ability to accept newly effluxed cholesterol from ATP-binding cassette A-I (ABCA1) to form nascent HDL (nHDL). New studies suggest that the Protein, procollagen c-endopeptidase Enhancer Protein 2 (PCOLCE2; PCPE2), is involved in mediating nHDL particle formation. PCPE2 is a 52 kDa glycoProtein sharing 43% amino acid identity with PCOLCE (PCPE1). Both are secreted into the extracellular matrix where they enhance the catalytic cleavage of the C-terminal propeptides of procollagen catalyzed by bone morphogenetic Protein 1 (BMP1). The connection between PCPE2 and HDL was discovered after significant correlations were found between single-nucleotide polymorphisms and plasma HDL-cholesterol concentrations in population studies. Consistent with these findings a recent genome-wide siRNA screening study indicated that PCPE2 was a significant modulator of HDL apoA-I secretion from cells, while other studies in mice lacking PCPE2 showed defective ABCA1-mediated cholesterol efflux, despite elevated plasma HDL. Thus, we began the current studies to determine if the increased plasma HDL, in light of defective cholesterol efflux, would be atheroprotective or atherogenic. PCPE2 null mice were crossed with LDL receptor null mice to obtain double knockout, LDLr -/- , PCPE2 -/- mice. Both LDLr -/- and LDLr -/- , PCPE2 -/- mice were fed an atherogenic diet for 12 wks after which the lipid deposition in the aortic root was evaluated. As expected, LDLr -/- , PCPE2 -/- mice showed elevated levels of enlarged HDL compared to control mice, while LDL levels were similar between the two genotypes. Despite elevations in plasma HDL, LDLr -/- , PCPE2 -/- mice showed significantly more atherosclerosis compared to LDLr -/- mice, similar in extent to that found in mice that lack HDL due to an absence of plasma apoA-I (LDLr -/- , apoA-I -/- ). This outcome suggests that PCPE2 is atheroprotective and likely participates at various levels of HDL metabolism, including HDL production, remodeling and catabolism.
Mary G Sorcithomas - One of the best experts on this subject based on the ideXlab platform.
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abstract 191 adipocyte procollagen c endopeptidase Enhancer Protein 2 pcpe2 influences lipid metabolism secondary to changes in expression and function of scavenger receptor class b member 1 sr bi
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Elisa Maruko, Sushma Kaul, Craig A Glastonbury, Kerrin S Small, Michael J Thomas, Michael Tschannen, Pengyuan Liu, Shirngwern Tsaih, Kaniz Fatema, Mary G SorcithomasAbstract:Scavenger receptor class B member 1 (SR-BI) functions as a HDL receptor and stimulates reverse cholesterol transport (RCT) via selective uptake of HDL cholesterol esters (HDL-CE). Procollagen c-endopeptidase Enhancer Protein 2 (PCPE2) is an extracellular matrix glycoProtein encoded by the PCOLCE2 gene and most highly expressed in adipose tissue, heart, and aorta. PCPE2 has been suggested to be atheroprotective secondary to mechanisms involved in lipid metabolism. Our lab previously reported that SR-BI mediated cholesterol ester uptake is reduced in the absence of PCPE2 despite its increased expression levels. Subsequent HDL turnover studies suggested an overall reduction in catabolism, consistent with larger HDL particles observed, is responsible for the paradox. More recently, human data from the TwinsUK study showed strong correlations between PCOLCE2 and adipose tissue distribution with BMI included as a covariate. Furthermore, despite similar overall body weights, our lab observed a significant reduction in visceral fat pad development in PCPE2-deficient mice fed a Western diet for 25 weeks when compared to wild type mice. In addition, our lab has generated PCPE2 knockout cell lines from murine preadipocyte 3T3-L1 cells (PCPE2 -/- 3T3-L1) and Chinese hamster ovary (CHO) cells using CRISPR-Cas9 and siRNA technology, respectfully. In addition to both cell lines showing increased SR-BI expression, differentiated PCPE2 -/- 3T3-L1 cells have impaired lipid droplet formation. To elucidate the relationship between PCPE2 and SR-BI function and their effects on adipose tissue development, we performed RNA sequencing on visceral adipose tissue from PCPE2-deficient male mice fed a Western diet for 12 weeks. Genes exhibiting significant expression alterations (FDR
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abstract 50 procollagen c endopeptidase Enhancer Protein 2 pcpe2 deficiency profoundly affects adipose distribution in mice and humans and links hdl metabolism to adipocyte biology
Arteriosclerosis Thrombosis and Vascular Biology, 2016Co-Authors: Sushma Kaul, Elisa Maruko, Mete Civelek, Craig A Glastonbury, Kerrin S Small, G M Dallingathie, Michael J Thomas, Ira J Goldberg, Mary G SorcithomasAbstract:Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) modulates selective HDL cholesterol ester uptake by SR-BI. Ldlr-/-,Pcpe2-/- mice develop greater aortic atherosclerosis despite increased concentrations of enlarged plasma HDL, suggesting PCPE2 confers functionality to HDL for reverse cholesterol transport. PCPE2 is a 52 kDa glycoProtein encoded by PCOLCE2 gene most highly expressed in adipose tissue, heart and aorta. PCPE2 has 2 CUB domains separated by a short linker, with each CUB domain containing a beta-sandwich fold, mediating a variety of Protein-Protein interactions. PCPE2 also contains a C-terminal netrin-like domain that binds tightly to cell surface glycosaminoglycans accounting for its location in the extracellular matrix. Because of the strong inverse correlation between HDL and triglyceride levels, and the potential role of SR-BI in triglyceride-rich lipoProtein uptake we examined Ldlr-/-,Pcpe2-/-mice fed a Western diet for 25 weeks. Ldlr-/-,Pcpe2-/- mice showed 1.7 fold increase in plasma triglyceride concentrations when compared to age and gender matched Ldlr-/- mice. We also noted that despite similar body weights, Ldlr-/-,Pcpe2-/- visceral fat pad weight was reduced 60% (p
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abstract 671 beyond cholesterol efflux defining hdl function in atherosclerosis and the requirement for procollagen c endopeptidase Enhancer Protein 2
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Ricquita D Pollard, Michael J Thomas, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mary G SorcithomasAbstract:Recent studies suggest that assessment of high density lipoProtein (HDL) function provides a more reliable metric of athero-protection than plasma concentration alone. One important function attributed to apolipoProtein A-I (apoA-I), the major Protein constituent of HDL, is its ability to accept newly effluxed cholesterol from ATP-binding cassette A-I (ABCA1) to form nascent HDL (nHDL). New studies suggest that the Protein, procollagen c-endopeptidase Enhancer Protein 2 (PCOLCE2; PCPE2), is involved in mediating nHDL particle formation. PCPE2 is a 52 kDa glycoProtein sharing 43% amino acid identity with PCOLCE (PCPE1). Both are secreted into the extracellular matrix where they enhance the catalytic cleavage of the C-terminal propeptides of procollagen catalyzed by bone morphogenetic Protein 1 (BMP1). The connection between PCPE2 and HDL was discovered after significant correlations were found between single-nucleotide polymorphisms and plasma HDL-cholesterol concentrations in population studies. Consistent with these findings a recent genome-wide siRNA screening study indicated that PCPE2 was a significant modulator of HDL apoA-I secretion from cells, while other studies in mice lacking PCPE2 showed defective ABCA1-mediated cholesterol efflux, despite elevated plasma HDL. Thus, we began the current studies to determine if the increased plasma HDL, in light of defective cholesterol efflux, would be atheroprotective or atherogenic. PCPE2 null mice were crossed with LDL receptor null mice to obtain double knockout, LDLr -/- , PCPE2 -/- mice. Both LDLr -/- and LDLr -/- , PCPE2 -/- mice were fed an atherogenic diet for 12 wks after which the lipid deposition in the aortic root was evaluated. As expected, LDLr -/- , PCPE2 -/- mice showed elevated levels of enlarged HDL compared to control mice, while LDL levels were similar between the two genotypes. Despite elevations in plasma HDL, LDLr -/- , PCPE2 -/- mice showed significantly more atherosclerosis compared to LDLr -/- mice, similar in extent to that found in mice that lack HDL due to an absence of plasma apoA-I (LDLr -/- , apoA-I -/- ). This outcome suggests that PCPE2 is atheroprotective and likely participates at various levels of HDL metabolism, including HDL production, remodeling and catabolism.
Sikandar L Katyal - One of the best experts on this subject based on the ideXlab platform.
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exogenous fibroblast growth factor 10 induces cystic lung development with altered target gene expression in the presence of heparin in cultures of embryonic rat lung
Pathobiology, 2012Co-Authors: Shuichi Hashimoto, Yuko Suguta, Seiko Irie, Hiroshi Nakano, Luo Jianhua, Sikandar L KatyalAbstract:Objectives: Signaling by fibroblast growth factor (FGF) receptor (FGFR) 2IIIb regulates branching morphogenesis in the mammalian lung. FGFR2IIIb is primarily expressed in epithelial cells, whereas its ligands, FGF-10 and keratinocyte growth factor (KGF; FGF-7), are expressed in mesenchymal cells. FGF-10 null mice lack lungs, whereas KGF null animals have normal lung development, indicating that FGF-10 regulates lung branching morphogenesis. In this study, we determined the effects of FGF-10 on lung branching morphogenesis and accompanying gene expression in cultures of embryonic rat lungs. Methods: Embryonic day 14 rat lungs were cultured with FGF-10 (0–250 ng/ml) in the absence or presence of heparin (30 ng/ml) for 4 days. Gene expression profiles were analyzed by Affymetrix microchip array including pathway analysis. Some of these genes, functionally important in FGF-10 signaling, were further analyzed by Northern blot, real-time PCR, in situ hybridization and immunohistochemistry. Results: Exogenous FGF-10 inhibited branching and induced cystic lung growth only in cultures containing heparin. In total, 252 upregulated genes and 164 downregulated genes were identified, and these included Spry1 (Sprouty-1), Spry2 (Sprouty-2), Spred-1, Bmp4 (bone morphogenetic Protein-4, BMP-4), Shh (sonic hedgehog, SHH), Pthlh (parathyroid hormone-related Protein, PTHrP), Dusp6 (MAP kinase phosphatase-3, MKP-3) and Clic4 (chloride intracellular channel-4, CLIC-4) among the upregulated genes and Igf1 (insulin-like growth factor-1, IGF-1), Tcf21 (POD), Gyg1 (glycogenin 1), Sparc (secreted Protein acidic and rich in cysteine, SPARC), Pcolce (procollagen C-endopeptidase Enhancer Protein, Pro CEP) and Lox (lysyl oxidase) among the downregulated genes. Gsk3β and Wnt2, which are involved in canonical Wnt signaling, were up- and downregulated, respectively. Conclusions: Unlike FGF-7, FGF-10 effects on lung branching morphogenesis are heparin-dependent. Sprouty-2, BMP-4, SHH, IGF-1, SPARC and POD are known to regulate branching morphogenesis; however, potential roles of CLIC-4 and MKP-3 in lung branching morphogenesis remain to be investigated. FGF-10 may also function in regulating branching morphogenesis or inducing cystic lung growth by inhibiting Wnt2/β-catenin signaling.
Brian Fulp - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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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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
Journal of Biological Chemistry, 2015Co-Authors: Ricquita D Pollard, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mark Gerelus, Xuewei Zhu, Nebil Nuradin, Daisy SahooAbstract: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 is a 52 kDa glycoProtein located in the extracellular matrix and enhances the cleavage of C-terminal procollagen by bone morphogenetic Protein 1 (BMP1). Our studies focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice and determining if 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 to 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 to 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 cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is athero-protective and it is an important component of the reverse cholesterol transport HDL system.
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abstract 671 beyond cholesterol efflux defining hdl function in atherosclerosis and the requirement for procollagen c endopeptidase Enhancer Protein 2
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Ricquita D Pollard, Michael J Thomas, Christopher N Blesso, Manal Zabalawi, Brian Fulp, Erica W Lyons, Omar L Francone, Mary G SorcithomasAbstract:Recent studies suggest that assessment of high density lipoProtein (HDL) function provides a more reliable metric of athero-protection than plasma concentration alone. One important function attributed to apolipoProtein A-I (apoA-I), the major Protein constituent of HDL, is its ability to accept newly effluxed cholesterol from ATP-binding cassette A-I (ABCA1) to form nascent HDL (nHDL). New studies suggest that the Protein, procollagen c-endopeptidase Enhancer Protein 2 (PCOLCE2; PCPE2), is involved in mediating nHDL particle formation. PCPE2 is a 52 kDa glycoProtein sharing 43% amino acid identity with PCOLCE (PCPE1). Both are secreted into the extracellular matrix where they enhance the catalytic cleavage of the C-terminal propeptides of procollagen catalyzed by bone morphogenetic Protein 1 (BMP1). The connection between PCPE2 and HDL was discovered after significant correlations were found between single-nucleotide polymorphisms and plasma HDL-cholesterol concentrations in population studies. Consistent with these findings a recent genome-wide siRNA screening study indicated that PCPE2 was a significant modulator of HDL apoA-I secretion from cells, while other studies in mice lacking PCPE2 showed defective ABCA1-mediated cholesterol efflux, despite elevated plasma HDL. Thus, we began the current studies to determine if the increased plasma HDL, in light of defective cholesterol efflux, would be atheroprotective or atherogenic. PCPE2 null mice were crossed with LDL receptor null mice to obtain double knockout, LDLr -/- , PCPE2 -/- mice. Both LDLr -/- and LDLr -/- , PCPE2 -/- mice were fed an atherogenic diet for 12 wks after which the lipid deposition in the aortic root was evaluated. As expected, LDLr -/- , PCPE2 -/- mice showed elevated levels of enlarged HDL compared to control mice, while LDL levels were similar between the two genotypes. Despite elevations in plasma HDL, LDLr -/- , PCPE2 -/- mice showed significantly more atherosclerosis compared to LDLr -/- mice, similar in extent to that found in mice that lack HDL due to an absence of plasma apoA-I (LDLr -/- , apoA-I -/- ). This outcome suggests that PCPE2 is atheroprotective and likely participates at various levels of HDL metabolism, including HDL production, remodeling and catabolism.