Wu Jinzi, Liu Shijie, Banerjee Oishani, Shi Hang, Xue Bingzhong, Ding Zufeng
Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
Theranostics. 2024 Mar 31;14(6):2427-2441. doi: 10.7150/thno.93036. eCollection 2024.
MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. MerTK is mainly expressed in macrophages and immature dendritic cells. There are very limited reports focused on MerTK biology in aortic endothelial cells (ECs). It remains unclear for the role of blood flow patterns in regulating MerTK-mediated efferocytosis in aortic ECs. This study was designed to investigate whether endothelial MerTK and EC efferocytosis respond to blood flow patterns during atherosclerosis. Big data analytics, RNA-seq and proteomics combined with our and studies were applied to reveal the potential molecular mechanisms. Partial carotid artery ligation combined with AAV-PCSK9 and high fat diet were used to set up acute atherosclerosis in 4 weeks. Our data showed that MerTK is sensitive to blood flow patterns and is inhibited by disturbed flow and oscillatory shear stress in primary human aortic ECs (HAECs). The RNA-seq data in HAECs incubated with apoptotic cells showed that d-flow promotes pro-inflammatory pathway and senescence pathway. Our data of proteomics and immunostaining showed that, compared with WT group, aggravates atherosclerosis in d-flow areas through upregulation of endothelial dysfunction markers (e.g. IL-1β, NF-κB, TLR4, MAPK signaling, vWF, VCAM-1 and p22) and mitochondrial dysfunction. Interestingly, induces obvious abnormal endothelial thickening accompanied with decreased endothelial efferocytosis, promoting the development of atherosclerosis. Our data suggests that blood flow patterns play an important role in regulating MerTK-mediated efferocytosis in aortic ECs, revealing a new promising therapeutic strategy with EC efferocytosis restoration to against atherosclerosis.
MER原癌基因酪氨酸激酶（MerTK）是胞葬作用的关键受体，胞葬作用是清除凋亡细胞的过程。MerTK主要在巨噬细胞和未成熟树突状细胞中表达。关于主动脉内皮细胞（ECs）中MerTK生物学的报道非常有限。目前尚不清楚血流模式在调节主动脉内皮细胞中MerTK介导的胞葬作用中的作用。本研究旨在探讨在动脉粥样硬化过程中，内皮MerTK和内皮细胞胞葬作用是否对血流模式有反应。我们运用大数据分析、RNA测序和蛋白质组学，并结合自身研究来揭示潜在的分子机制。采用部分颈动脉结扎联合腺相关病毒载脂蛋白PCSK9和高脂饮食在4周内建立急性动脉粥样硬化模型。我们的数据表明，MerTK对血流模式敏感，在原代人主动脉内皮细胞（HAECs）中，紊乱血流和振荡剪切应力会抑制其表达。与凋亡细胞共孵育的HAECs的RNA测序数据表明，紊乱血流促进促炎途径和衰老途径。我们蛋白质组学和免疫染色的数据表明，与野生型组相比，在紊乱血流区域，通过上调内皮功能障碍标志物（如白细胞介素-1β、核因子κB、Toll样受体4、丝裂原活化蛋白激酶信号通路、血管性血友病因子、血管细胞黏附分子-1和p22）和线粒体功能障碍，加重动脉粥样硬化。有趣的是，会导致明显的内皮异常增厚，同时内皮细胞胞葬作用降低，促进动脉粥样硬化的发展。我们的数据表明，血流模式在调节主动脉内皮细胞中MerTK介导的胞葬作用中起重要作用，揭示了一种通过恢复内皮细胞胞葬作用来对抗动脉粥样硬化的新的有前景的治疗策略。
