Shear-Induced ITGB4 Promotes Endothelial Cell Inflammation and Atherosclerosis

Abstract

The local heterogeneity in the distribution of atherosclerotic lesions is caused by local flow patterns. The integrin family plays crucial regulatory roles in diverse biological processes, but knowledge of integrin β4 (ITGB4) in shear stress-induced atherosclerosis is limited. This study clarified that low shear stress (LSS) regulates the generation of ITGB4 in endothelial cells with atheroprone phenotype to identify ITGB4’s role in atherosclerosis. We found that LSS led to an increase in ITGB4 protein expression both in vitro and in vivo. ITGB4 knockdown attenuated inflammation and ROS generation in human umbilical vein endothelial cells (HUVECs) and reduced atherosclerotic lesion areas in ApoE-/- mice fed with HFD, largely independent of effects on the lipid profile. Mechanistically, ITGB4 knockdown altered the phosphorylation levels of SRC, FAK, and NFκB in HUVECs under LSS conditions. In addition, the knockdown of NFκB inhibited the production of ITGB4 and SRC phosphorylation, and the knockdown of SRC downregulated ITGB4 protein expression and NFκB activation. These data demonstrate a critical role of ITGB4 in atherosclerosis via modulation of endothelial cell inflammation, and ITGB4/SRC/NFκB might form a positive feedback loop in the regulation of endothelial cell inflammation.

Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications

“…The β4, α6β1, and β3 integrins that are present on ECs and VSMCs play roles in the inflammation and plaque formation of AS. Research has shown that β4 integrins on the plasma membrane of ECs activates a positive feedback signaling pathway by activating SRC and downstream NF-κB, the activation of which contributes to excessive transcriptional activity of β4 integrins; the activation of the pathway then upregulates the expression of endothelial inflammatory factors, leading to the development of AS (Figure 2) [38]. Furthermore, a similar mechanism has been reported in which the α6β1 integrins present on ECs bind to the EC-expressed matrix protein CCN1 to activate NF-κB, which forms a positive feedback loop with the CCN1 and α6β1 integrins and amplifies oxidative stress and inflammation in the arterial wall (Figure 2) [39].…”

The site-specific distribution of atheromatous plaques in the coronary arteries

“…In vitro and in vivo experiments showed that ECs are critical sensors of shear stress that modulate endothelial structure, function, and permeability [ 59 ]. Low or low and oscillatory WSS triggers multiple pathways of intracellular signaling pathways that promote the expression of pro-proliferative and pro-inflammatory mechanosensitive genes while suppressing atheroprotective flow-dependent genes [ 60 ]. As a result, a flow-dependent inflammatory and infiltrative process is initiated with important implications for hemostasis and thrombosis, vascular tone, redox balance, vascular smooth cell proliferation and ultimately their osteoblastic transformation with subsequent plaque calcification [ 47 ].…”