The subendothelial extracellular matrix modulates JNK activation by flow.
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.
Hahn
Cornelia
C
Department of Microbiology, University of Virginia, Charlottesville, VA 22908-0734, USA.
Orr
A Wayne
AW
Sanders
John M
JM
Jhaveri
Krishna A
KA
Schwartz
Martin Alexander
MA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001485:Basement Membrane / Q000378:metabolism; D002417:Cattle; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D018056:Hemorheology; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016023:Integrins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009991:Oscillometry; D010766:Phosphorylation; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D054462:p21-Activated Kinases / Q000378:metabolism
D001057:Apolipoproteins E; D005353:Fibronectins; D016023:Integrins; D003094:Collagen; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases