Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Clin Sci (Lond). 2020 Sep 18;134(17):2353-2368. doi: 10.1042/CS20191241.
Genetic variants in phosphatase and actin regulator-1 (Phactr1) are reported to be associated with arteriosclerotic cardiovascular disease (ASCVD). However, the function of Phactr1 in atherosclerosis remains unclear. Patients with acute coronary syndrome (ACS) who underwent coronary angiography and optical coherence tomography (OCT) were enrolled and divided into non-ST segment elevation (NST-ACS) group and ST-ACS group. The expression of Phactr1 on monocytes was higher in NST-ACS and ST-ACS groups as compared with control group. Furthermore, NST-ACS patients who have more vulnerable features including thin-cap fibroatheroma (TCFA) and large lipid area showed higher levels of Phactr1 on monocytes than those with stable plaques. Through mouse models of atherosclerosis, Phactr1-/-Apoe-/- mice (double knockout mice, DKO) developed more severe atherosclerotic plaques, recruiting more macrophages into subendothelium and having elevated levels of proinflammatory cytokines in plaques. Similarly, Apoe knockout mice (Apoe-/-) receiving DKO bone marrow (BM) exhibited elevated plaque burden compared with Apoe-/- mice receiving Apoe-/- BM, indicating the protective effect of Phactr1 in hematopoietic cells. We found that depletion of Phactr1 in BM-derived macrophages (BMDMs) tended to differentiate into M1 phenotype, produced more proatherogenic cytokines and eventually converted into foam cells driven by oxidized low-density lipoprotein (ox-LDL). Mechanistically, Phactr1 activated CREB signaling via directly binding to CREB, up-regulating CREB phosphorylation and inducing KLF4 expression. Finally, overexpression of KLF4 partly rescued the excessive inflammation response and foam cell formation induced by deficiency of Phactr1. In conclusion, our study demonstrates that elevated Phactr1 in monocytes is a promising biomarker for vulnerable plaques, while increased Phactr1 attenuates atherosclerotic development via activation of CREB and M2 macrophage differentiation.
磷酸酶和肌动蛋白调节因子-1（Phactr1）的遗传变异被报道与动脉粥样硬化性心血管疾病（ASCVD）有关。然而，Phactr1 在动脉粥样硬化中的功能仍不清楚。接受冠状动脉造影和光相干断层扫描（OCT）的急性冠状动脉综合征（ACS）患者被纳入并分为非 ST 段抬高（NST-ACS）组和 ST 段抬高（ST-ACS）组。与对照组相比，NST-ACS 和 ST-ACS 组单核细胞上的 Phactr1 表达更高。此外，与稳定斑块患者相比，具有更多易损特征（包括薄帽纤维粥样瘤（TCFA）和大脂质区）的 NST-ACS 患者，其单核细胞上的 Phactr1 水平更高。通过动脉粥样硬化小鼠模型，Phactr1-/-Apoe-/-小鼠（双敲除小鼠，DKO）发展出更严重的动脉粥样硬化斑块，更多的巨噬细胞招募到内膜下，并在斑块中升高促炎细胞因子水平。同样，接受 DKO 骨髓（BM）的 Apoe 敲除小鼠（Apoe-/-）比接受 Apoe-/-BM 的 Apoe-/-小鼠表现出更高的斑块负担，表明 Phactr1 在造血细胞中具有保护作用。我们发现，BM 来源的巨噬细胞（BMDMs）中 Phactr1 的耗竭倾向于分化为 M1 表型，产生更多促动脉粥样硬化的细胞因子，并最终在氧化低密度脂蛋白（ox-LDL）的驱动下转化为泡沫细胞。机制上，Phactr1 通过直接与 CREB 结合激活 CREB 信号，上调 CREB 磷酸化并诱导 KLF4 表达。最后，过表达 KLF4 部分挽救了 Phactr1 缺乏引起的过度炎症反应和泡沫细胞形成。总之，我们的研究表明，单核细胞中升高的 Phactr1 是易损斑块的有前途的生物标志物，而增加的 Phactr1 通过激活 CREB 和 M2 巨噬细胞分化来减轻动脉粥样硬化的发展。
