CXCL12 Derived From Endothelial Cells Promotes Atherosclerosis to Drive Coronary Artery Disease

Abstract

Genome-wide association studies (GWAS) have established a link between the genomic locus 10q11, which hosts the CXCL12 gene, and the risk for coronary artery disease (CAD) (1). CAD risk alleles downstream of CXCL12 have been associated with plasma levels of the chemokine CXCL12 (2); however, the nature and directionality of this association remain elusive. Recently, a Mendelian randomization study identifying genetic determinants of biomarkers in the populations of ORIGIN and CARDIoGRAM revealed CXCL12 as a causal mediator of CAD, supported by epidemiological analysis showing a 15% higher risk for cardiovascular events per SD of increased CXCL12 plasma levels in ORIGIN (3). To detail the association between CXCL12 and CAD, we conducted a meta-analysis of GWAS performed in the EPIC-Norfolk and PROMIS cohorts (n=12,657; filters: INFO≥0.5, MAF≥0.01, HWE≥1×10 −6 , only SNPs appearing in both cohorts). The study was approved by an institutional review committee and subjects gave informed consent. Applying conditional analysis, we newly identified rs2802492, an intergenic SNP near CXCL12, to be independently associated with CXCL12 plasma levels (β=0.016, P=3.24×10 −8) as determined by ELISA (α-isoform, R&D Systems Quantikine kit) (2) and with increased risk for CAD (OR 1.047, P=1.27×10 −6), corroborating CXCL12 as a driver of CAD. No linkage disequilibrium (r 2 >0.8) was found between rs2802492 and the CAD-associated SNPs rs1746048 (1) and intergenic rs1482478 (3). Notably, when specifically tested for

High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis

“…Thus far, we have validated significant KO‐specific increases in expression for 10 genes identified by NanoString analysis (Figure 5B,C), most of which have been previously shown to have proven roles in the pathogenesis of atherosclerosis. These include (i) von Willebrand factor (VWF), an endothelial‐associated factor that facilitates platelet interactions and early atherogenesis 64 ; (ii) Lipocalin (LCN) 2, which promotes polarization and migration of plaque macrophages 65 ; (iii) Endoglin, an endothelial and SMC protein with a positive role in the pathogenesis of atherosclerosis 66 ; (iv) S100a8, a protein that is expressed by inflammatory macrophages and promotes atherosclerosis 67 ; (v) CCL2 (monocyte chemoattractant protein‐1), a chemokine with a fundamental role in monocyte recruitment in the subendothelium (an early event in atherosclerosis) 68,69 ; and (vi‐vii) CXCL12 70 and Pecam1, 71 which are both endothelium cell‐derived factors known to promote atherosclerosis and to be strongly associated with coronary artery diseases as shown by the presence of several SNPs in patients from multiple populations 72 . It is important to note that the GAIT element‐mediated atheroprotective mechanism that we have identified relies on L13a‐dependent translational silencing of target genes 11 .…”

Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review

“…For instance, Kaasinen and collaborators observed an increased expression of chemokine receptor type 4 (CXCR4) in individuals with germinal TET2 mutation that, since CXCR4 exerts an anti-atherosclerotic effect by preserving vascular function in arteries [50], may counterbalance the pro-atherosclerotic effect. In a recent paper, Doring and collaborators [51] demonstrated that CXCR4, the receptor of CXCL12 (whose expression and plasma levels were previously associated with coronary artery disease [52,53]), was able to confer cell-specific athero-protective effects preserving endothelial function in mice.…”

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

“…The source of the ligand for CXCR4, CXCL12 is another interest for future studies. Recently, elevated blood CXCL12 level has been identified as a risk factor of coronary artery disease (54,55) and endothelial specific CXCL12 deletion was reported to accelerate plaque progression in murine atherosclerosis model (55), which is the opposite effect to endothelial CXCR4. However, CXCL12 has another receptor CXCR7 expressed on ECs (34) which regulates systemic CXCL12 level (56).…”