Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans
Background—Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor but the underlying mechanisms responsible for its pathogenicity are poorly defined. Since Lp(a) is the prominent carrier of pro-inflammatory oxidized phospholipids (OxPL), part of its atherothrombosis might be mediated through this pathway.
Methods—In vivo imaging techniques MR imaging, 18F-FDG-PET/CT and SPECT/CT were used to measure subsequently atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed using FACS analysis, inflammatory stimulation assays and transendothelial migration assays. In vitro studies to the pathophysiology of Lp(a) on monocytes were performed using an in vitro model for trained immunity.
Results—We show that subjects with elevated Lp(a) (108 [50-195] mg/dL; n=30) have increased arterial inflammation and enhanced PBMCs trafficking to the arterial wall, compared with subjects with normal Lp(a) (7 [2-28] mg/dL; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce pro-inflammatory cytokines upon stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the pro-inflammatory response in monocytes derived from healthy controls (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apo(a). Conclusions—These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.
Clinical Trial Registration—URL: http://www.trialregister.nl; Unique Identifier: NTR5006 (VIPER study)
- Received October 1, 2015.
- Revision received June 3, 2016.
- Accepted June 22, 2016.