Published online before print March 12, 2009, doi: 10.1161/CIRCRESAHA.108.186486
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Submitted on August 27, 2008
Revised on February 23, 2009
Accepted on February 26, 2009
The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow
Cornelia Hahn ;
From the Departments of Microbiology (C.H., M.A.S.), Cell Biology (M.A.S.), and Biomedical Engineering (M.A.S.); Robert M. Berne Cardiovascular Research Center (J.M.S., K.A.J., M.A.S.); and Mellon Urological Cancer Research Center (M.A.S.), University of Virginia, Charlottesville; and Department of Pathology (A.W.O.), Louisiana State University Health Sciences Center, Shreveport.
* To whom correspondence should be addressed. E-mail: maschwartz{at}virginia.edu.
Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. The 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.
Key words: shear stress • atherosclerosis • JNK
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