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.
Highlights
Extracellular matrix protein procollagen C-endopeptidase enhancer protein2 (PCPE2) is linked to alterations in HDL size and concentration
We have suggested mechanisms to explain the role of PCPE2 and provided evidence demonstrating the participation of PCPE2 in HDL cholesterol catabolism and reverse cholesterol transport
Upon overexpression of PCPE2, a shift to one population with a significantly higher frequency of SR-BI/cell is observed (50992 Ϯ 1070 versus 36244 Ϯ 905, mean Ϯ S.D., n ϭ 3 independent experiments). These results suggest that PCPE2 may act to enhance SR-BI function by promoting or maintaining SR-BI expression on the cell surface
Summary
Extracellular matrix protein PCPE2 is linked to alterations in HDL size and concentration. In humans there is an inverse correlation between the concentration of plasma HDL and the relative risk of developing cardiovascular disease (CVD)5 [1,2,3,4] To explain this association, many studies have suggested that HDL plays a central role in the pathway called reverse cholesterol transport (RCT), a process that returns cholesterol to the liver for excretion [5, 6]. ATP-binding cassette transporter A1 (ABCA1) lipidates apoA-I with phospholipid and cholesterol to form nascent HDL (nHDL) [5, 7,8,9]. We have suggested mechanisms to explain the role of PCPE2 and provided evidence demonstrating the participation of PCPE2 in HDL cholesterol catabolism and reverse cholesterol transport
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
