Diabetology & metabolic syndrome · 2025
Mechanisms and clinical translation of ICOS/ICOSL signaling pathway blockade in delaying vascular complications of type 2 diabetes.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Haiyan, Ruan LiBo, Fu Xuemei, Yu Jinwen, Ruan Qingrong, Li Yiyu, Wang Hongying, Shao Heng, Dong Haoran, Cui Jianglan
Аннотация
BACKGROUND: Type 2 diabetes mellitus (T2DM) is often complicated by vascular conditions such as atherosclerosis, which contribute significantly to morbidity and mortality. The ICOS/ICOSL signaling pathway has emerged as a promising target for mitigating these complications. This study aims to investigate the effects of ICOS/ICOSL pathway blockade on vascular inflammation and endothelial dysfunction in T2DM and atherosclerosis, and to assess its potential for clinical translation.
METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from T2DM patients, with and without atherosclerosis (AS), as well as healthy controls. ICAM-1 and VCAM-1 levels were measured by ELISA, and RNA sequencing was conducted to identify differentially expressed genes. In an animal model, diabetic mice were treated with ICOS-Fc fusion protein to block ICOS/ICOSL signaling. Endothelial dysfunction was modeled in mouse C166 cells and primary Human Umbilical Vein Endothelial Cells (HUVECs) using high glucose (HG), and the effects of ICOS-Fc on cell migration, angiogenesis, ROS production, apoptosis, and key signaling molecules were analyzed.
RESULTS: ICAM-1 and VCAM-1 levels were significantly elevated in both the T2DM and AS groups compared to controls. In vivo, treatment with ICOS-Fc not only reduced the expression of ICOS, ICOSL, ICAM-1, and VCAM-1 in the aortic tissue of diabetic mice but also significantly ameliorated hyperlipidemia and reduced atherosclerotic plaque burden. In HG-treated C166 cells, ICOS-Fc reduced ROS production and apoptosis while enhancing cell migration and angiogenesis. Crucially, in HUVECs, ICOS-Fc treatment reversed HG-induced inflammatory gene expression and restored angiogenic capacity, a benefit associated with the normalization of endothelial nitric oxide synthase (eNOS) phosphorylation.
CONCLUSION: Blocking the ICOS/ICOSL signaling pathway effectively mitigates vascular inflammation and endothelial dysfunction in T2DM with atherosclerosis. These findings suggest that targeting this pathway holds promise as a novel therapeutic strategy for managing vascular complications in T2DM.
METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from T2DM patients, with and without atherosclerosis (AS), as well as healthy controls. ICAM-1 and VCAM-1 levels were measured by ELISA, and RNA sequencing was conducted to identify differentially expressed genes. In an animal model, diabetic mice were treated with ICOS-Fc fusion protein to block ICOS/ICOSL signaling. Endothelial dysfunction was modeled in mouse C166 cells and primary Human Umbilical Vein Endothelial Cells (HUVECs) using high glucose (HG), and the effects of ICOS-Fc on cell migration, angiogenesis, ROS production, apoptosis, and key signaling molecules were analyzed.
RESULTS: ICAM-1 and VCAM-1 levels were significantly elevated in both the T2DM and AS groups compared to controls. In vivo, treatment with ICOS-Fc not only reduced the expression of ICOS, ICOSL, ICAM-1, and VCAM-1 in the aortic tissue of diabetic mice but also significantly ameliorated hyperlipidemia and reduced atherosclerotic plaque burden. In HG-treated C166 cells, ICOS-Fc reduced ROS production and apoptosis while enhancing cell migration and angiogenesis. Crucially, in HUVECs, ICOS-Fc treatment reversed HG-induced inflammatory gene expression and restored angiogenic capacity, a benefit associated with the normalization of endothelial nitric oxide synthase (eNOS) phosphorylation.
CONCLUSION: Blocking the ICOS/ICOSL signaling pathway effectively mitigates vascular inflammation and endothelial dysfunction in T2DM with atherosclerosis. These findings suggest that targeting this pathway holds promise as a novel therapeutic strategy for managing vascular complications in T2DM.