Reduced Notch1 Cleavage Promotes the Development of Pulmonary Hypertension.
Reduced Notch1 Cleavage Promotes the Development of Pulmonary Hypertension.
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DOI：
10.1161/hypertensionaha.120.16065
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Pang J
中科院分区：
文献类型：
--
作者：
Wang S;Zhu G;Jiang D;Rhen J;Li X;Liu H;Lyu Y;Tsai P;Rose Y;Nguyen T;White RJ;Pryhuber GS;Mariani TJ;Li C;Mohan A;Xu Y;Pang J
Delta-like 4(DLL4)中和抗体(DLL4nAbs)在癌症患者中的临床试验正在进行中。令人惊讶的是，接受D114nAbs治疗的患者中有14%-18%发生了肺动脉高压(PH)，但其机制尚未被研究。在这里，测量了用D114nAbs治疗的小鼠的PH进展。检测肺组织中的Notch信号，分析肺血管通透性和炎症反应。应用Notch靶向基因芯片技术，对抑制Notch裂解后的成人肺微血管内皮细胞(HPMECs)进行研究。在PH小鼠模型和PAH患者中也进行了类似的机制研究。此外，还检测了Notch1在体内的救治效果。我们观察到，D114nAbs诱导了小鼠肺动脉高压，表现为右室收缩压显着增加，以及肺血管和右室重构。从机制上讲，D114nAbs抑制Notch1的裂解，继而损害肺内皮细胞屏障功能，增加免疫细胞在血管壁的渗透。在体外，Notch1失活后HPMECs中与细胞生长和炎症相关的Notch靶向基因的表达减少。在PH小鼠模型和PAH患者的肺中，Notch1裂解被抑制。在PH小鼠模型中，EC细胞-细胞连接始终是漏的，免疫细胞浸润增加。过度表达激活的Notch1可以延缓小鼠肺高压的进展。综上所述，D114nAbs通过损伤EC屏障功能和通过抑制肺内皮细胞Notch1裂解而增加免疫细胞的渗透，从而导致小鼠肺高压的发生。肺内皮细胞Notch1裂解减少可能是PH发病机制之一。持续而有力地减少肺内皮细胞中Notch1的裂解是PH发病的一个新的分子机制。
Clinical trials of Delta-like 4 (Dll4) neutralizing antibodies (Dll4nAbs) in cancer patients are ongoing. Surprisingly, pulmonary hypertension (PH) occurs in 14-18% of patients treated with Dll4nAbs, but the mechanisms have not been studied. Here, PH progression was measured in mice treated with Dll4nAbs. We detected Notch signaling in lung tissues and analyzed pulmonary vascular permeability and inflammation. Notch target gene array was performed on adult human pulmonary microvascular endothelial cells (HPMECs) after inhibiting Notch cleavage. Similar mechanisms were studied in PH mouse models and PAH patients. The rescue effects of constitutively activated Notch1 in vivo were also measured. We observed that Dll4nAbs induced PH in mice as indicated by significantly increased right ventricular systolic pressure as well as pulmonary vascular and right ventricular remodeling. Mechanistically, Dll4nAbs inhibited Notch1 cleavage and subsequently impaired lung endothelial barrier function and increased immune cell infiltration in vessel walls. In vitro, Notch targeted genes’ expression related to cell growth and inflammation was decreased in HPMECs after the Notch1 inactivation. In lungs of PH mouse models and PAH patients, Notch1 cleavage was inhibited. Consistently, EC cell-cell junction was leaky, and immune cell infiltration increased in PH mouse models. Overexpression activated Notch1 attenuated the progression of PH in mice. In conclusion, Dll4nAbs led to PH development in mice by impaired EC barrier function and increased immune cell infiltration through inhibition of Notch1 cleavage in lung ECs. Reduced Notch1 cleavage in lung ECs could be an underlying mechanism of PH pathogenesis. Consistently and robustly reduced Notch1 cleavage in pulmonary endothelial cells is a novel molecular mechanism of PH pathogenesis.
影响因子：
5
作者：
Pang J;Xu X;Getman MR;Shi X;Belmonte SL;Michaloski H;Mohan A;Blaxall BC;Berk BC
通讯作者：
Berk BC