Atherosclerosis is characterized by the build-up of fat-rich deposits (‘plaques’) on the inner surface of endothelial cells lining the blood vessels. The presence of these plaques is associated with a chronic inflammatory reaction, which can ultimately result in constriction of the vessel and the obstruction of blood flow in major arteries leading to coronary artery disease.
IPEK researchers among whom Dr. Yvonne Döring, Dr. Emiel van der Vorst and Prof. Christian Weber investigated the contribution of a class of signal proteins known as chemokines to the pathogenesis of atherosclerosis. Chemokines are small proteins released by various types of immune cells, which interact with specific receptors found on the surfaces of these same immune cells. In their work, recently published in Circulation the scientists further elucidated the role of the chemokine CXCL12 and its involvement in coronary artery disease (CAD). Genome-wide association studies have established a link between the CXCL12 gene, and the risk for CAD. In this context CAD risk alleles downstream of CXCL12 have been associated with plasma levels of the chemokine CXCL12; however, the nature and directionality of this association remained elusive. In their study, the researchers took advantage of meta-analysis of genome wide association studies performed in the EPIC-Norfolk and PROMIS cohorts (more than 12.000 individuals), to identify an intergenic single nucleotide polymorphism (rs2802492), near CXCL12, as independently and significantly associated with CXCL12 plasma levels andincreased risk for CAD. These findings were further validated in atherosclerosis in a set of animals carrying cell-specific CXCL12-deficiencies e.g. in hematopoietic, vascular smooth muscle or endothelial cells. They were able to show that effects of CXCL12 on atherosclerosis rely on CXCL12 produced by arterial endothelial cells, identifying endothelial CXCL12 as a crucial driver of atherosclerosis and contributor to CXCL12 levels.
