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Low shear stress-induced blockage of autophagic flux impairs endothelial barrier and facilitates atherosclerosis in mice.
Cao, Ruhao; Sun, Ruxian; Ye, Yuanzhi; Tian, Pingge; Huang, Bin; Ye, Haowen; Dai, Libing; Lan, Zirong; Liu, Jia; Li, Li.
Afiliação
  • Cao R; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Sun R; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Ye Y; Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, 510280, Ch
  • Tian P; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Huang B; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Ye H; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Dai L; Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • Lan Z; Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, 510280, Ch
  • Liu J; VIP Medical Service Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China. Electronic address: liuj683@mail.sysu.edu.cn.
  • Li L; Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China. Electronic address: lilygs@ext.jnu.edu.cn.
Exp Cell Res ; 439(1): 114071, 2024 Jun 01.
Article em En | MEDLINE | ID: mdl-38729336
ABSTRACT
Atherosclerosis preferentially occurs in areas with low shear stress (LSS) and oscillatory flow. LSS has been demonstrated to correlate with the development of atherosclerosis. The sphingosine 1-phosphate receptor 1 (S1PR1), involving intravascular blood flow sensing, regulates vascular development and vascular barrier function. However, whether LSS affects atherosclerosis via regulating S1PR1 remains incompletely clear. In this study, immunostaining results of F-actin, ß-catenin, and VE-cadherin indicated that LSS impaired endothelial barrier function in human umbilical vein endothelial cells (HUVECs). Western blot analysis showed that LSS resulted in blockage of autophagic flux in HUVECs. In addition, autophagy agonist Rapamycin (Rapa) antagonized LSS-induced endothelial barrier dysfunction, whereas autophagic flux inhibitor Bafilomycin A1 (BafA1) exacerbated it, indicating that LSS promoted endothelial barrier dysfunction by triggering autophagic flux blockage. Notably, gene expression analysis revealed that LSS downregulated S1PR1 expression, which was antagonized by Rapa. Selective S1PR1 antagonist W146 impaired endothelial barrier function of HUVECs under high shear stress (HSS) conditions. Moreover, our data showed that expression of GAPARAPL2, a member of autophagy-related gene 8 (Atg8) proteins, was decreased in HUVECs under LSS conditions. Autophagic flux blockage induced by GAPARAPL2 knockdown inhibited S1PR1, aggravated endothelial barrier dysfunction of HUVECs in vitro, and promoted aortic atherosclerosis in ApoE-/- mice in vivo. Our study demonstrates that autophagic flux blockage induced by LSS downregulates S1PR1 expression and impairs endothelial barrier function. GABARAPL2 inhibition is involved in LSS-induced autophagic flux blockage, which impairs endothelial barrier function via downregulation of S1PR1.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Estresse Mecânico / Aterosclerose / Células Endoteliais da Veia Umbilical Humana / Receptores de Esfingosina-1-Fosfato Limite: Animals / Humans / Male Idioma: En Revista: Exp Cell Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Estresse Mecânico / Aterosclerose / Células Endoteliais da Veia Umbilical Humana / Receptores de Esfingosina-1-Fosfato Limite: Animals / Humans / Male Idioma: En Revista: Exp Cell Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China