Jeffrey Kroon, Netherlands
University Medical Center Amsterdam Department of Vascular MedicinePresenter of 1 Presentation
Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation
Abstract
Background and Aims
Patients with elevated levels of Lp(a) are hallmarked by increased arterial wall inflammation on 18F-FDG PET/CT, which has been shown to predict future cardiovascular risk. The endothelium is the first line of defence against pro-inflammatory changes in the artery wall. Recent evidence suggested that lipids may induce a pro-inflammatory state by altering intracellular metabolic responses. Therefore, we hypothesized that Lp(a) mediates endothelial inflammation via metabolic reprogramming, facilitating a pro-inflammatory environment, thereby driving monocyte migration through the vessel wall.
Methods
RNAseq, Metabolic-Flux-Analysis, TEM, qPCR, atherosclerosis-biobank
Results
In-depth RNA-sequencing of Human Arterial Endothelial Cells (HAECs) stimulated with Lp(a) significantly induced inflammatory pathways involved in efficient leukocyte adhesion and migration. This was confirmed by targeted qPCR, attested by a significant increase in leukocyte adhesion molecules MCP-1, ICAM-1, VCAM-1 (2.9, 5.0 and 3.1-fold increase in gene-expression, respectively) with a concomitant 7.1-fold increase in monocyte transendothelial migration (TEM).This inflammatory endothelial phenotype coincided with increased expression of key glycolytic genes PFKFB3, HK2 and PFKM (2.9, 2.3 and 2.1-fold increase respectively), whereas glycolytic flux analysis corroborated an 85% increase in glycolytic activity. Pharmacological inhibition of inducible glycolysis (PFKFB3) by PFK158 abolished the inflammatory signature and reduced TEM by 75%. These findings were substantianted using a large Atherosclerotic Endarterectomy Biobank (Athero-Express).
Conclusions
This data is the first that shows that Lp(a) activates the endothelium by enhancing inducible-glycolysis, leading to induction of a pro-adhesive state which can be reversed by specific inhibition of inducible-glycolysis. This novel finding paves the way for therapeutic agents targeting metabolic reprogramming to reduce the pro-inflammatory state in cardiovascular-patients.