Abstract 17146: Lipoprotein (a) Induces Monocyte Activation and Arterial Wall Inflammation via Epigenetic Remodeling
Introduction: Lipoprotein (a) [Lp(a)] is causally related to atherosclerosis, the mechanism of which remains to be established. Novel insight was gained by the finding that Lp(a) is the major carrier of oxidized phospholipids, which are damaging molecules that elicit vascular inflammation. Therefore, we hypothesized that Lp(a) induces monocyte activation and arterial wall inflammation.
Methods: First, we assessed the effect of Lp(a) on monocytes in vitro. Monocytes were exposed to Lp(a) for 24 hours and after 6 days, cells were restimulated with TLR agonists to assess cytokine production, mRNA expression and trimethylation of lysine 4 at histone 3 (H3K4me3). Second, we characterized monocytes of 24 subjects with elevated Lp(a) (>50mg/dL) and 12 matched controls ex vivo via flowcytometry, monocyte migration assay, cytokine production and H3K4me3. Third, the clinical relevance was evaluated in vivo via (i) single-photon emission computed tomography (SPECT) for tracing of 99Technetium-labelled autologous monocytes and (ii) positron emitting tomography (PET) for arterial wall FDG uptake.
Results: First, we found that exposure of monocytes to Lp(a) increased pro-atherogenic cytokine production and mRNA expression caused by an increased H3K4me3, which was absent in pretreatment with a histone methyltransferase inhibitor. Second, we showed that isolated monocytes of Lp(a) subjects exhibit a higher expression of adhesion markers, corresponding to enhanced transendothelial migration. In line with our in vitro studies, we found that monocytes of Lp(a) subjects produce more pro-atherogenic cytokines, accompanied by increased H3K4me3. Translating these findings, we thirdly demonstrated in Lp(a) subjects that autologous monocytes traced via SPECT accumulated in the arterial wall, resulting in enhanced arterial wall FDG uptake as assessed with PET.
Conclusions: In conclusion, Lp(a) elicits prolonged monocyte activation via epigenetic remodeling, resulting in accelerated monocyte influx and increased arterial wall inflammation in vivo. These data imply that Lp(a)-induced cellular and arterial wall inflammation may contribute to the increased cardiovascular risk, thereby offering novel therapeutic targets in humans with elevated Lp(a).
Author Disclosures: F. van der Valk: None. S. Bekkering: None. J. Kroon: None. N. Riksen: None. M. Nieuwdorp: None. S. Tsimikas: None. J. van Buul: None. M. Netea: None. E. Stroes: Research Grant; Modest; Netherlands CardioVascular Research Initiative, Bristol Myers Squib.
- © 2014 by American Heart Association, Inc.