Inducible reduction in pregnancy-associated plasma protein-A gene expression inhibits established atherosclerotic plaque progression in mice

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase implicated in cardiovascular disease. The aim of this study was to determine whether a reduction in PAPP-A expression in the adult affects the progression of established atherosclerotic plaque. Apolipoprotein E-null mice were fed a high-fat diet for 5 weeks to initiate early-stage plaque development before tamoxifen-inducible, Cre recombinase-mediated excision of the floxed PAPP-A gene. High-fat feeding was continued, and after 10 weeks the aorta and brachiocephalic artery were harvested for atherosclerotic plaque analyses of overall burden and morphology, respectively. An inducible decrease in PAPP-A gene expression significantly inhibited atherosclerotic plaque progression as assessed by a 70% reduction in plaque burden in the aorta (P = .012) without an effect on the elevated circulating levels of cholesterol and triglycerides in this model. Furthermore, this reduction in PAPP-A prevented the development of advanced plaque with necrotic cores and buried fibrous caps in the brachiocephalic artery. These data indicate PAPP-A as a potential target to limit progression of established atherosclerotic plaque.

Figure 1.

Representative en face Sudan IV-stained aortas from ApoE-null mice with fPAPP-A and negative or positive for Tam-Cre.

Figure 2.

Quantitated plaque area (A) and plaque number (B) in aortas from ApoE-null mice with fPAPP-A and negative or positive for Tam-Cre. All mice were administered Tam as described in Materials and Methods. Results are means ± SEM of 17 (fPAPP-A/Neg) and 18 (fPAPP-A/Pos) mice. *, Significantly different from fPAPP-A/Neg, P = .012.

Figure 3.

Quantitated plaque area (A) and plaque number (B) in aortas from ApoE-null mice with WT PAPP-A and negative or positive for Tam-Cre. All mice were administered Tam as described in Materials and Methods. Results are means ± SEM of 7 (fPAPP-A/Neg) and 8 (fPAPP-A/Pos) mice.

Figure 4.

Masson trichrome staining of brachiocephalic arteries from ApoE-null fPAPP-A/Neg mice (A and B) and an ApoE-null fPAPP-A/Pos mouse (C). Yellow asterisks indicate necrotic cores. Green arrows indicate examples of buried fibrous caps.