Abstract
Macrophage migration inhibitory factor (MIF) is a non-canonical cytokine that is involved in multiple inflammatory diseases, including atherosclerosis. High MIF expression found in leukocytes which facilitates the initiation and progression of atherosclerosis. However, little is known about biomechanical forces in the induction of MIF in endothelial cells (ECs). Here, we show that laminar shear stress (LS) inhibits the expression of MIF in ECs. By profiling the whole transcriptome of human coronary artery ECs under different shear stress, we found that athero-protective LS attenuates the expression of MIF whereas pro-atherosclerotic oscillatory shear stress (OS) significantly increased the expression of MIF. En face staining of rabbit aorta revealed high MIF immunoreactivity in lesser curvature as well as arterial bifurcation areas where OS is predominant. Mechanistically, we found that Krüpple like factor 2 (KLF2) is required for inhibition of MIF expression in ECs in the context of shear stress. Knockdown of KLF2 abolishes LS-dependent MIF inhibition while overexpression of KLF2 significantly attenuated MIF expression. Overall, the present work showed that MIF is a shear stress-sensitive cytokine and is transcriptionally regulated by KLF2, suggesting that LS exerts its athero-protective effect in part by directly inhibiting pro-inflammatory MIF expression.
Highlights
Given the high atherosclerotic susceptibility in oscillatory shear stress (OS)-exposed areas, studies have demonstrated that pro-inflammatory factors induced by OS are actively involved in the process of atherosclerosis[8]
We focused on the shear stress-induced inflammatory genes in endothelial cells (ECs) considering that atherosclerosis is well-recognized as a chronic inflammatory disease[20]
A great number of studies focus on the causes and pathogenesis of atherosclerosis, with variations in the hemodynamic forces generated by blood flow long recognized as a primary driver of atherosclerosis and responsible for the non-random topography of the lesions[10]
Summary
Given the high atherosclerotic susceptibility in OS-exposed areas, studies have demonstrated that pro-inflammatory factors induced by OS are actively involved in the process of atherosclerosis[8]. High MIF expression level in atherosclerotic lesions is found in animal models[14] as well as human subjects[15]. Studies have further demonstrated that blockage of MIF in macrophages reduces the formation of atherosclerotic lesions in atherosclerotic animal models[16,17]. The mechanisms regulating MIF expression in ECs remain elusive. We hypothesized that EC-specific MIF, a pro-inflammatory cytokine, contributes to the process of atherosclerosis with its atherogenic effect naturally inhibited by LS in vivo. The present work provides direct evidence to show that biomechanical activation is essential in regulating the pro-atherosclerotic cytokine MIF. This natural protective mechanism of LS may shed light towards the development of anti-atherosclerotic therapeutics
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