Inhibition of c-Jun N-Terminal Kinase Attenuates Low Shear Stress-Induced Atherogenesis in Apolipoprotein E-Deficient Mice
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.
This work was supported by the National 973 Basic Research Program of China (2009CB521900), the National High-Tech Research and Development Program of China (2006AA02A406), the Program of Introducing Talents of Discipline to Universities (B07035), the State Program of National Natural Science Foundation of China for Innovative Research Group (81021001), the State Key Program of National Natural Science of China (60831003), and the National Natural Science Foundation of China (30900607, 30871037 and 30772810).
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