Kettunen Sanna, Ruotsalainen Anna-Kaisa, Örd Tiit, Suoranta Tuisku, Heikkilä Janne, Kaikkonen Minna U, Laham-Karam Nihay, Ylä-Herttuala Seppo
A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
Front Cardiovasc Med. 2023 Mar 6;10:1113890. doi: 10.3389/fcvm.2023.1113890. eCollection 2023.
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.
This study aimed to investigate the role of the murine ortholog of human 9p21.3 locus in atherogenesis in hypercholesterolemic mice.
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.
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.
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.
多项全基因组关联研究报告称，9p21.3染色体区域存在冠状动脉疾病（CAD）风险位点。该区域在INK4基因座中编码一种长链非编码RNA（lncRNA），其遗传变异与CAD密切相关，但其在动脉粥样硬化发生中的机制尚不清楚。
本研究旨在探讨人类9p21.3基因座的小鼠直系同源物在高胆固醇血症小鼠动脉粥样硬化发生中的作用。
将小鼠9p21.3直系同源基因敲除小鼠（Chr4）与 小鼠杂交，并在标准饮食或高脂饮食（HFD）条件下分析动脉粥样硬化斑块的大小和形态。通过骨髓（BM）移植研究Chr4对造血细胞特异性动脉粥样硬化斑块发展的影响，即将Chr4或野生型BM移植到 小鼠体内。研究Chr4在巨噬细胞M1/M2极化中的作用。此外，分析来自人和小鼠动脉粥样硬化斑块的单细胞测序数据，以显示 和其小鼠等效物 在斑块中的表达谱。
在高脂饮食12周后，全身性和造血性Chr4均增加了 小鼠的动脉粥样硬化。全身性Chr4还增加了循环白细胞的数量。Chr4骨髓来源的巨噬细胞（BMDMs）显示出增强的M1极化 。来自人和小鼠动脉粥样硬化斑块的单细胞测序数据显示， 和 主要在免疫细胞中表达。
这些数据表明，小鼠9p21.3风险位点直系同源物的全身性和BM特异性缺失均促进动脉粥样硬化并调节巨噬细胞的促炎活性，提示该风险位点在动脉粥样硬化发生中存在炎症驱动机制。
