Search

Introduction: Elevated lipoprotein(a) [Lp(a)] has emerged as a highly prevalent, independent factor causing both a systemic pro-inflammatory state and eventually a markedly elevated risk for cardiovascular events. The exact molecular mechanisms underlying the atherogenicity of Lp(a) of endothelial cells, the first line defence against atherogenesis, remain largely unknown. In view of the abundance of oxidized phospholipids (OxPL) on Lp(a), we set out to evaluate whether metabolic reprogramming by Lp(a) contributed to the pro-inflammatory state of the endothelium. Methods: Human Arterial Cells (HAEC) were stimulated with Lp(a) (50-1000 mg/L). Subsequently, Lp(a)-induced metabolic reprogramming and its concomitant inflammatory signature was assessed using RNA sequencing and Seahorse Flux analysis. To validate these findings and their functionality, we performed targeted qPCR, Immunoblotting and monocyte transendothelial migration (TEM) assays. Results: Lp(a) was found to induce an inflammatory response in HAEC, 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 TEM. These pro-inflammatory changes coincided with the induction of glycolytic activity by Lp(a), comprising increased gene-expression of the key glycolytic enzymes PFKFB3, PFKM, HK2 (2.3, 2.9 and 2.1-fold increase respectively), which was accompanied by an increase in glucose uptake and lactate production (27% and 84% respectively). Glycolytic inhibition by the inducible glycolysis inhibitor PFK158 abolished the inflammatory signature and reduced TEM by 75%. Blocking oxPL-Lp(a) signaling by the monoclonal antibody E06 reduced inducible glycolysis by 47%, inflammation and monocyte TEM by 42%. Similar levels of LDL-C had no significant impact on either metabolic reprogramming or the inflammatory response. Conclusion: Lp(a) induces metabolic reprogramming in ECs, which induces a pro-inflammatory phenotype in the endothelium. This inflammatory response is mediated by OxPLs carried on Lp(a), facilitating a profound migratory response of circulating monocytes. This data implies that inhibition of inducible glycolysis may be an attractive target to attenuate inflammatory activity in patients with elevated Lp(a). [ABSTRACT FROM AUTHOR]