Abstract 320: Procollagen C-Endopeptidase Enhancer Protein 2 Enhances SR-BI Mediated HDL Cholesterol Uptake and Reduces Atherosclerosis in Mice
| Autor: | Ricquita D. Pollard, Brian Fulp, Omar L. Francone, Manal Zabalawi, Nebil Nuradin, Erica L. Lyons, Michael J. Thomas, Mark Gerelus, Daisy Sahoo, Christopher N. Blesso, Xiang-An Li, Xuewei Zhu |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
medicine.diagnostic_test Cholesterol Reverse cholesterol transport nutritional and metabolic diseases Transfection Biology Bone morphogenetic protein 1 chemistry.chemical_compound Procollagen peptidase Endocrinology High-density lipoprotein chemistry Western blot Internal medicine medicine lipids (amino acids peptides and proteins) Scavenger receptor Cardiology and Cardiovascular Medicine |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 35 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Epidemiological studies have shown an inverse correlation between plasma high density lipoprotein (HDL) concentrations and cardiovascular disease risk. At variance with these observations, clinical trials that significantly raised plasma HDL-C levels did not have improved clinical outcomes, emphasizing the importance of understanding HDL function. Recently, a significant correlation has been reported between human procollagen c-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and HDL. PCPE2, a 52 kDa glycoprotein found in the extracellular matrix enhances cleavage of C-terminal procollagen by bone morphogenetic protein 1. Mice lacking PCPE2 have elevated concentrations of enlarged plasma HDL, a phenomenon associated with defective cholesterol efflux. HDL synthesis depends on ABCA1-mediated lipid efflux to lipid-poor apoA-I balanced by cholesterol uptake through hepatic scavenger receptor class B type I (SR-BI). Our studies focused on investigating if the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice was atheroprotective. PCPE2 deficient mice were crossed with LDLr -/- mice (SKO) giving LDLr -/- , PCPE2 -/- (DKO) mice that had elevated HDL levels compared to SKO mice. Despite elevated HDL levels, we found that DKO mice had significantly more lipid and CD68+ infiltration into the aortic root, similar to that reported for LDLr -/- , apoA-I -/- mice that lack plasma apoA-I/HDL. Furthermore, DKO mice showed reduced HDL apoA-I fractional clearance and reverse cholesterol transport rates compared to SKO mice suggesting PCPE2 plays a significant role in HDL remodeling and/or cholesterol uptake by the liver. To test the effect of PCPE2 on SR-BI function we incubated 3 H-cholesteryl ether ( 3 H-CE) enriched HDL from SKO and DKO mice with CHO cells overexpressing PCPE2. Compared to CHO control cells, overexpression of PCPE2 increased 3 H-CE HDL uptake that was independent of HDL particle origin. Western Blot analysis showed no difference in SR-BI expression between control and PCPE2 transfected cells, suggesting that PCPE2 enhanced SR-BI function and promoted HDL cholesterol ester uptake. We conclude that PCPE2 is atheroprotective and an essential component of the reverse cholesterol transport system. |
| Databáze: | OpenAIRE |
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