Abstract 10833: Increased Inflammatory State in ATP-Binding Cassette Transporter A1 Mutation Carriers
Introduction: We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to its role in reverse cholesterol transport. More recently, a pro-inflammatory effect of ABCA1 deficiency was shown in mice, contributing to a pro-atherogenic state. In the present study, we evaluated whether ABCA1 deficiency is associated with pro-inflammatory changes in humans.
Material and methods: 21 heterozygous and 4 homozygous ABCA1 mutation carriers as well as 21 matched controls were subjected to a PET-CT scan to assess arterial wall inflammation (target-background-ratio, TBR). Plasma cytokines and mRNA expression of inflammatory genes in monocytes were assessed. The mechanism of action was evaluated in vitro, by measuring mRNA expression in THP1 cells following incubation with plasma or apoB depleted plasma from ABCA1 mutation carriers versus non-carrier plasma and ABCA1 siRNA knockdown experiments respectively.
Results: ABCA1 mutation carriers had a significantly higher TBR compared to controls (TBR 1.62±0.16 versus 1.34±0.16; p=0.006). In carriers using statins TBR was 27% reduced compared to non-statin users (p=0.03). In plasma, TNFα and MCP1 levels showed a gene-dose dependent increase in controls, heterozygous and homozygous carriers, with a concomitant 2 to 4-fold increased inflammatory cytokine mRNA expression in monocytes from carriers.
Mechanistically, plasma isolated from ABCA1 mutation carriers induced a 2 to 7-fold gene-dose dependent increase in inflammatory cytokine mRNA expression in THP1 cells. ApoB depletion did not change this effect. In addition, ABCA1 knockdown markedly increased inflammatory cytokine mRNA expression in THP1 cells, which was attenuated after pre-incubation with recombinant HDL.
Conclusion: We show a marked pro-inflammatory state in ABCA1 mutation carriers, as reflected by plasma cytokine levels in ABCA1 mutation carriers as well as increased arterial wall inflammation. The latter is likely due to increased levels of circulating cytokines, secondary to a direct effect of cellular ABCA1 deficiency. This data supports the development and application of anti-inflammatory compounds in cardiovascular risk reduction.
- © 2013 by American Heart Association, Inc.