Shear-Induced ITGB4 Promotes Endothelial Cell Inflammation and Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Integrin Signaling

Background:

• Atherosclerosis pathogenesis is influenced by endothelial cell responses to biomechanical forces, particularly shear stress.
• The role of integrin beta4 (ITGB4) in shear stress-mediated endothelial dysfunction and atherosclerosis remains poorly understood.

Purpose of the Study:

• To investigate the regulation of ITGB4 by low shear stress (LSS) in endothelial cells.
• To elucidate the functional role of ITGB4 in the development of atherosclerosis.
• To identify the molecular mechanisms linking ITGB4 to endothelial inflammation under LSS.

Main Methods:

• In vitro studies using human umbilical vein endothelial cells (HUVECs) exposed to LSS.
• In vivo experiments using apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD).
• ITGB4 knockdown using siRNA, assessment of inflammation, reactive oxygen species (ROS) generation, atherosclerotic lesion area, and Western blot analysis of signaling proteins (SRC, FAK, NFκB).

Main Results:

• LSS significantly increased ITGB4 protein expression in HUVECs and in vivo.
• ITGB4 knockdown attenuated LSS-induced inflammation and ROS production in HUVECs.
• ITGB4 knockdown reduced atherosclerotic lesion size in ApoE-/- mice without significantly altering lipid profiles.
• ITGB4 knockdown affected the phosphorylation of SRC, FAK, and NFκB under LSS; NFκB and SRC knockdown modulated ITGB4 expression and activation of the signaling pathway.

Conclusions:

• Integrin beta4 (ITGB4) plays a critical role in promoting endothelial cell inflammation and atherosclerosis development under low shear stress conditions.
• The ITGB4/SRC/NFκB signaling axis forms a positive feedback loop regulating endothelial inflammation in response to shear stress.
• Targeting ITGB4 may represent a novel therapeutic strategy for atherosclerosis.