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Circ Res. 2009 Apr 24;104(8):995-1003. doi: 10.1161/CIRCRESAHA.108.186486. Epub 2009 Mar 12.

The subendothelial extracellular matrix modulates JNK activation by flow.

Author information

1
Department of Microbiology, University of Virginia, Charlottesville, VA 22908-0734, USA.

Abstract

Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH(2)-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.

PMID:
19286608
PMCID:
PMC2702158
DOI:
10.1161/CIRCRESAHA.108.186486
[Indexed for MEDLINE]
Free PMC Article
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