Journal
CIRCULATION RESEARCH
Volume 104, Issue 8, Pages 995-U180Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.186486
Keywords
shear stress; atherosclerosis; JNK
Funding
- US Public Health Service [R01 HL75092]
- NIH [5T32-HL007284-28, -29, -30]
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Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH2-terminal kinase) is thought to be among the major regulators of flow-dependent inflammatory gene expression in endothelial cells in atherosclerosis. We now show that JNK activation by both onset of laminar flow and long-term oscillatory flow is matrix-specific, with enhanced activation on fibronectin compared to basement membrane protein or collagen. Flow-induced JNK activation on fibronectin requires new integrin ligation and requires both the mitogen-activated protein kinase kinase MKK4 and p21-activated kinase. In vivo, JNK activation at sites of early atherogenesis correlates with the deposition of fibronectin. Inhibiting p21-activated kinase reduces JNK activation in atheroprone regions of the vasculature in vivo. These results identify JNK as a matrix-specific, flow-activated inflammatory event. Together with other studies, these data elucidate a network of matrix-specific pathways that determine inflammatory events in response to fluid shear stress. (Circ Res. 2009; 104: 995-1003.)
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