Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.
Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.
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DOI：
10.1038/s41467-023-39586-z
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发表时间：
2023-07-25
影响因子：
16.6
通讯作者：
Shaul, Philip W.
中科院分区：
文献类型：
--
作者：
Yu, Liming;Xu, Lin;Chu, Haiyan;Peng, Jun;Sacharidou, Anastasia;Hsieh, Hsi-hsien;Weinstock, Ada;Khan, Sohaib;Ma, Liqian;Duran, Jose Gabriel Barcia;McDonald, Jeffrey;Nelson, Erik R.;Park, Sunghee;McDonnell, Donald P.;Moore, Kathryn J.;Huang, Lily Jun-shen;Fisher, Edward A.;Mineo, Chieko;Huang, Linzhang;Shaul, Philip W.
高胆固醇血症和血管炎症是动脉粥样硬化发病机制的关键相互关联的贡献者。高胆固醇血症如何引发血管炎症尚不清楚。在这里，我们表明在雄性小鼠中，高胆固醇血症驱动的内皮细胞活化，单核细胞募集和动脉粥样硬化病变的形成是由胆固醇代谢产物27-羟基胆固醇（27 HC）介导的巨噬细胞和内皮细胞之间的串扰促进的。巨噬细胞衍生的27 HC的促动脉粥样硬化作用需要内皮雌激素受体α（ERα）和细胞质支架蛋白Septin 11从ERα解离，导致NF-κB的细胞核ERα和Septin 11依赖性活化。此外，产生27 HC的cyp 27 a1的药理学抑制通过减少内皮活化和单核细胞募集提供动脉粥样硬化保护。这些发现证明了27 HC的细胞间通讯，并确定了高胆固醇血症和血管炎症之间的主要因果关系，从而促进动脉粥样硬化。中断这种联系的干预措施可以提供一种手段，以钝化血管炎症，而不损害宿主防御，以打击动脉粥样硬化性心血管疾病的风险，尽管降脂治疗仍然存在。高胆固醇血症和血管炎症均参与动脉粥样硬化的发病机制，但高胆固醇血症如何引发血管炎症尚不完全清楚。在这里，作者报告说，由胆固醇代谢物27-羟基胆固醇介导的巨噬细胞和内皮细胞之间的串扰驱动血管炎症，并导致雄性小鼠的动脉粥样硬化。
Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies. Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
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影响因子：
20.1
作者：
Afonso MS;Sharma M;Schlegel M;van Solingen C;Koelwyn GJ;Shanley LC;Beckett L;Peled D;Rahman K;Giannarelli C;Li H;Brown EJ;Khodadadi-Jamayran A;Fisher EA;Moore KJ
通讯作者：
Moore KJ
影响因子：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
影响因子：
--
作者：
DuSell, Carolyn D.;Umetani, Michihisa;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
37.8
作者：
Billon-Gales, Audrey;Fontaine, Coralie;Arnal, Jean-Francois
通讯作者：
Arnal, Jean-Francois