ECM-specific endothelial inflammatory signaling: regulation by integrin alpha5 interaction with PDE4D

Youn, S., Budatha, M., Baillie, G. and Schwartz, M. (2014) ECM-specific endothelial inflammatory signaling: regulation by integrin alpha5 interaction with PDE4D. In: Vascular Matrix Biology and Bioengineering Workshop IV and Biology of Signaling in the Cardiovascular System Workshop III, Hyannis, MA, USA, 20-24 Oct 2013, p. 313. (doi:10.1007/s10456-013-9412-3)

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Abstract

Previous work has shown that ECM remodeling is a key component of the inflammatory activation of the endothelium in atherosclerosis, which occurs in regions of arteries subject to disturbed flow. Fibronectin is deposited in these atherosclerosis-prone regions of arteries even in WT mice. Fluid shear-dependent inflammatory signaling mediated by NF-jB or JNK is selectively induced in endothelial cells on fibronectin whereas it is suppressed on basement membrane proteins. Investigation of the mechanism behind these effects showed that PKA is selectively activated in cells on basement membrane and suppresses inflammatory signaling. We therefore investigated the integrin receptors that mediate ECM binding. The major fibronectin receptor, a5b1, and the major collagen/laminin receptor, a2b1, share the common b1 subunit. We therefore analyzed the cytoplasmic domains of the unique integrin alpha subunits. A chimera in which the integrin a5 cytosolic tail was replaced by the a2 cytosolic tail was examined. Endothelial cells expressing the integrin a5/2 chimera adhered and spread normally on fibronectin. However, shear stress activated PKA and inhibited NF-jB, similar to cells on basement membranes. Pharmacological inhibition of PDE4 activity abolished fibronectin-specific NF-jB activation, indicating that cAMP degradation is required for the pro-inflammatory effects of fibronectin. PDE4D5 directly and specifically associates with the integrin a5 cytosolic tail. Knock-down of PDE4D impaired flow-dependent NFjB activation in the cells on fibronectin. These data suggest that the interaction of the integrin a5 cytoplasmic domain with PDE4D mediates the pro-inflammatory effects of fibronectin by inhibiting the anti-inflammatory cAMP/PKA pathway.

Item Type:Conference Proceedings
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George
Authors: Youn, S., Budatha, M., Baillie, G., and Schwartz, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
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