G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction

Tianhan Li; Juhui Qiu; Tingting Jia; Yinming Liang; Kun Zhang; Wenhua Yan; Zhengjun Hou; Shiwei Yang; Lushan Liu; Wenhao Xiong; Yaokai Chen; Guixue Wang

doi:10.1016/j.gendis.2021.11.003

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction

Genes Dis. 2021 Nov 19;9(6):1701-1715. doi: 10.1016/j.gendis.2021.11.003. eCollection 2022 Nov.

Authors

Tianhan Li^{1

2}, Juhui Qiu¹, Tingting Jia², Yinming Liang², Kun Zhang¹, Wenhua Yan¹, Zhengjun Hou¹, Shiwei Yang³, Lushan Liu⁴, Wenhao Xiong⁴, Yaokai Chen⁵, Guixue Wang¹

Affiliations

¹ Key Laboratory for Biorheological Science and Technology of Ministry of Education, State Key Laboratory of Mechanical Transmission, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing 400044, PR China.
² Laboratory of Genetic Regulators in the Immune System, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 45003, PR China.
³ Department of Vascular Surgery, First Affiliated Hospital, Army Medical University (Third Military University), Chongqing 400038, PR China.
⁴ Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, PR China.
⁵ Division of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing 400030, PR China.

Abstract

GTPase-activating SH3 domain-binding protein 2 (G3BP2) is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases. However, no studies have examined the contribution of G3BP2 in the oscillatory shear stress (OSS)-induced endothelial dysfunction. Here we assessed the effects of G3BP2 in endothelial cells (ECs) function and investigated the underlying mechanism. Using shear stress apparatus and partial ligation model, we identified that stress granule-related genes in ECs could be induced by OSS with RNA-seq, and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions. G3bp2 ^-/- Apoe ^-/- mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function, decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels. Furthermore, loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation. These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

Keywords: Atherosclerosis; Endothelial cells (ECs); G3BP2; Oscillatory shear stress (OSS); YAP.