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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025322 | PMC |
| http://dx.doi.org/10.3389/fcvm.2023.1113890 | DOI Listing |
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