Herbin Olivier, Regelmann Adam G, Ramkhelawon Bhama, Weinstein Erica G, Moore Kathryn J, Alexandropoulos Konstantina
From the Icahn School of Medicine at Mount Sinai, Department of Medicine, The Immunology Institute, New York (O.H., E.G.W., K.A.); Quartzy, Inc, Palo Alto, CA (A.G.R.); and Leon H. Charney Division of Cardiology, Department of Medicine, NYU School of Medicine, New York (B.R., K.J.M.).
Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1791-801. doi: 10.1161/ATVBAHA.116.308014. Epub 2016 Jul 14.
The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell-specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development.
Using Chat-H-deficient bone marrow transplantation in low-density lipoprotein receptor-deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6c(high) and nonclassical Ly6c(low) monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This associated with defective adhesion of Chat-H-deficient Ly6c(high) and Ly6c(low) monocytes to vascular cell adhesion molecule-1 in vitro and impaired infiltration of fluorescent bead-loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes.
Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis.
与动脉粥样硬化相关的慢性炎症是由脂质沉积后白细胞募集至动脉壁所致。我们之前表明造血细胞特异性衔接蛋白Cas-和Hef1相关信号转导子造血异构体（Chat-H）/SHEP1调节淋巴细胞黏附和迁移。在本研究中，我们分析了Chat-H在动脉粥样硬化发展中的作用。
利用Chat-H缺陷型骨髓移植到低密度脂蛋白受体缺陷小鼠中，我们发现Chat-H调节动脉粥样硬化斑块形成。造血细胞中Chat-H缺陷与较低的斑块复杂性和病变中较少的白细胞相关，而Chat-H的髓系特异性缺失足以赋予抗动脉粥样硬化保护作用。Chat-H缺陷导致经典的Ly6c（高）和非经典的Ly6c（低）单核细胞向斑块的募集减少，同时血液中这两种单核细胞亚群的数量增加。这与Chat-H缺陷的Ly6c（高）和Ly6c（低）单核细胞在体外对血管细胞黏附分子-1的黏附缺陷以及荧光珠负载的单核细胞向动脉粥样硬化斑块的浸润受损有关。相比之下，Chat-H对于单核细胞的CX3CL1和CCR1/CCR5依赖性迁移是可有可无的。
我们的研究结果突出了Chat-H作为一种关键蛋白，通过控制单核细胞黏附和向斑块的募集来调节动脉粥样硬化的发展，并确定了一个可用于治疗动脉粥样硬化的新靶点。
