Deletion of the murine ortholog of human 9p21.3 locus promotes atherosclerosis by increasing macrophage proinflammatory activity.

BACKGROUND

Several genome-wide association studies have reported a risk locus for coronary artery disease (CAD) in the 9p21. 3 chromosomal region. This region encodes a lncRNA in the INK4 locus () and its genetic variance has a strong association with CAD, but its mechanisms in atherogenesis remain unclear.

OBJECTIVES

This study aimed to investigate the role of the murine ortholog of human 9p21.3 locus in atherogenesis in hypercholesterolemic mice.

METHODS

Murine 9p21.3 ortholog knockout mice (Chr4 ) were crossbred with mice, and atherosclerotic plaque size and morphology were analyzed on a standard or a high-fat diet (HFD). The hematopoietic cell-specific effect of Chr4 on atherosclerotic plaque development was studied bone marrow (BM) transplantation, where Chr4 or wild-type BM was transplanted into mice. The role of Chr4 in macrophage M1/M2 polarization was studied. In addition, single-cell sequencing data from human and mouse atheroma were analyzed to show the expression profiles of and its murine equivalent, , in the plaques.

RESULTS

Both systemic and hematopoietic Chr4 increased atherosclerosis in mice after 12 weeks of HFD. The systemic Chr4 also elevated the number of circulating leukocytes. Chr4 BMDMs showed enhanced M1 polarization . Single-cell sequencing data from human and mouse atheroma revealed that and were mainly expressed in the immune cells.

CONCLUSION

These data demonstrate that both systemic and BM-specific deletion of the murine 9p21.3 risk locus ortholog promotes atherosclerosis and regulates macrophage pro-inflammatory activity, suggesting the inflammation-driven mechanisms of the risk locus on atherogenesis.