Abstract 671: Beyond Cholesterol Efflux: Defining HDL Function in Atherosclerosis and the Requirement for Procollagen C-Endopeptidase Enhancer Protein 2

Abstract

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.