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Orr et al. (page 191) show that the composition of the subendothelial extracellular matrix (ECM) controls whether NF-B, a major inflammatory response protein, is activated by fluid shear stress.Atherosclerosis typically occurs in regions of disturbed blood flow, such as vascular branch points. Integrins become activated in response to increased flow, converting the proteins to a high-affinity conformation. Once activated, integrins bind to the subendothelial ECM and initiate intracellular signaling. Additionally, the binding of some integrins, but not all, triggers NF-B signaling. Others have observed that NF-B signaling in the endothelium contributes to the initiation of atherosclerosis. Now, Orr et al. have connected these observations.1 b6 S" f- M& `9 x
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In an in vitro system, they found that NF-B was activated in response to flow when cells were plated on fibronectin or fibrinogen, which are associated with damage or inflammation, but not when they were grown on collagen or laminin, which are the primary matrix components in healthy vasculature. In vivo, fibronectin and markers of NF-B activation were found together in the subendothelial ECM in regions of disturbed flow even in mice that were resistant to atherosclerosis. Both ECM changes and expression of NF-B markers were accelerated in ApoE-null mice as they developed arthrosclerosis. If the team altered the structure of the matrix proteins, they reduced NF-B signaling in response to flow.
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The new results do not provide an immediate prevention strategy for atherosclerosis, but they do suggest a novel target for therapies. Knowing that different components of the subendothelial matrix result in different responses to flow means that, if researchers can find a way to maintain the innocuous matrix proteins or alter matrix properties to prevent NF-B activation, they may be able to slow the disease.(Fibronectin (brown) helps induce signali) |
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发表于 2009-3-6 08:42
发表于 2015-5-22 16:01
