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Papers In Press, published online ahead of print January 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800119-JLR200

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Journal of Lipid Research, Vol. 50, 81-89, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

LDLs stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase

Natasa Bulat^*, Gérard Waeber and Christian Widmann^1,*

^* Department of Physiology and Department of Cell Biology and Morphology, Lausanne University, 1005 Lausanne, Switzerland
Department of Internal Medicine, University Hospital Center, and University of Lausanne, Lausanne, Switzerland

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.

Published, JLR Papers in Press, August 28, 2008.

This work is supported by grants from the Swiss National Science Foundation.

¹ To whom correspondence should be addressed. e-mail: Christian.Widmann{at}unil.ch

Intracellular signals elicited by LDLs are likely to play a role in the pathogenesis associated with increased LDL blood levels. We have previously determined that LDL stimulation of human skin fibroblasts, used as a model system for adventitial fibroblasts, activates p38 mitogen-activated protein kinases (MAPKs), followed by IL-8 production and increased wound-healing capacity of the cells. The proximal events triggering these responses had not been characterized, however. Here we show that MAPK kinases MKK3 and MKK6, but not MKK4, are the upstream kinases responsible for the activation of the p38 MAPKs and stimulation of wound closure in response to LDLs. Phosphoinositide 3 kinases (PI3Ks) and Ras have been suggested to participate in lipoprotein-induced MAPK activation. However, specific PI3K inhibitors or expression of a dominant-negative form of Ras failed to blunt LDL-induced p38 MAPK activation. The classical LDL receptor does not participate in LDL signaling, but the contribution of other candidate lipoprotein receptors has not been investigated. Using cells derived from scavenger receptor class B type I (SR-BI) knockout mice or the BLT-1 SR-BI inhibitor, we now show that this receptor is required for LDLs to stimulate p38 MAPKs and to promote wound healing. Identification of MKK3/6 and SR-BI as cellular relays in LDL-mediated p38 activation further defines the signaling events that could participate in LDL-mediated pathophysiological responses.

Supplementary key words scavenger receptor class B type I • mitogen-activated protein kinase • fibroblasts

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