Abstract
Atherosclerosis begins as local inflammation of arterial walls at sites of disturbed flow, such as vessel curvatures and bifurcations with low shear stress. c-Jun NH₂-terminal kinase (JNK) is a major regulator of flow-dependent gene expression in endothelial cells in atherosclerosis. However, little is known about the in vivo role of JNK in low shear stress in atherosclerosis. We aimed to observe the effect of JNK on low shear stress-induced atherogenesis in apolipoprotein E-deficient (ApoE(-/-)) mice and investigate the potential mechanism in human umbilical vein endothelial cells (HUVECs). We divided 84 male ApoE(-/-) mice into two groups for treatment with normal saline (NS) (n = 42) and JNK inhibitor SP600125 (JNK-I) (n = 42). Perivascular shear stress modifiers were placed around the right carotid arteries, and plaque formation was studied at low shear stress regions. The left carotid arteries without modifiers represented undisturbed shear stress as a control. The NS group showed atherosclerotic lesions in arterial regions with low shear stress, whereas the JNK-I group showed almost no atherosclerotic lesions. Corresponding to the expression of proatherogenic vascular cell adhesion molecule 1 (VCAM-1), phospho-JNK (p-JNK) level was higher in low shear stress regions with NS than with JNK-I inhibitor. In HUVECs under low shear stress, siRNA knockdown and SP600125 inhibition of JNK attenuated nuclear factor (NF)-κB activity and VCAM-1 expression. Furthermore, siRNA knockdown of platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31) reduced p-JNK and VCAM-1 levels after low shear stress stimulation. JNK may play a critical role in low shear stress-induced atherogenesis by a PECAM-1-dependent mechanosensory pathway and modulating NF-κB activity and VCAM-1 expression.
Highlights
Atherosclerotic lesions form preferentially at distinct sites in the arterial tree, especially at or near branch points, bifurcations and inner curvatures, where there is low or oscillatory blood flow
SP600125 had no significant effect on lipid levels in the circulation system, and diet or lipid levels did not contribute to the observed atherosclerotic lesion differences between two groups
We confirmed that low shear stress was essential in plaque formation, and inhibition of Jun NH2-terminal kinase (JNK) markedly reduced low shear stress–induced plaque formation in ApoE–/– mice
Summary
Atherosclerotic lesions form preferentially at distinct sites in the arterial tree, especially at or near branch points, bifurcations and inner curvatures, where there is low or oscillatory blood flow (that is, displaying directional change and boundary layer separation). Shear stress is critically important in regulating the vascular physiology and pathobiology of the vessel wall by modulating endothelial cell (EC) function [1,2,3,4]. Previous investigators showed that the expression of vascular cell adhesion molecule 1 (VCAM-1) and monocyte binding were increased in rabbit carotids chronically exposed to low shear stress compared with normal shear stress [6]. Cheng et al [10] developed a perivascular shear stress modifier (called a cast) that could induce changes in shear stress patterns in a straight vessel and used the model to assess the effect of shear stress alterations on the development of atherosclerosis in apolipoprotein E deficient (ApoE–/–) mice. The authors found that atherosclerotic lesions developed under low and oscillatory shear stress but not increased shear stress
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