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Papers In Press, published online ahead of print December 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300266-JLR200

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Journal of Lipid Research, Vol. 44, 2382-2390, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

LDLs induce fibroblast spreading independently of the LDL receptor via activation of the p38 MAPK pathway

Iveta Dobreva^*, Gérard Waeber, Vincent Mooser, Richard W. James^1, and Christian Widmann^1,2,*

^* Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Switzerland
Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Lipid Laboratory, Clinical Diabetes Unit, University Hospital, Geneva, Switzerland

² To whom correspondence should be addressed. e-mail: christian.widmann{at}ibcm.unil.ch

Because adventitial fibroblasts play an important role in the repair of blood vessels, we assessed whether elevation in LDL concentrations would affect fibroblast function and whether this depended on activation of intracellular signaling pathways. We show here that in primary human fibroblasts, LDLs induced transient activation of the p38 mitogen-activated protein kinase (MAPK) pathway, but not the c-Jun N-terminal kinase MAPK pathway. This activation did not require the recruitment of the LDL receptor (LDLR), because LDLs efficiently stimulated the p38 MAPK pathway in human and mouse fibroblasts lacking functional LDLR, and because receptor-associated protein, an LDLR family antagonist, did not block the LDL-induced p38 activation. LDL particles also induced lamellipodia formation and cell spreading. These effects were blocked by SB203580, a specific p38 inhibitor.

Our data demonstrate that LDLs can regulate the shape of fibroblasts in a p38 MAPK-dependent manner, a mechanism that may participate in wound healing or vessel remodeling as in atherosclerosis.

Abbreviations: FACS, fluorescent-activated cell sorter; FCS, fetal calf serum; FH, familial hypercholesterolemia; HS, human serum; JNK, c-Jun N-terminal kinase; LDLR, LDL receptor; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; RAP, receptor-associated protein; SAPK, stress-activated protein kinase; SREBP, sterol-regulatory element binding protein

Supplementary key words remodeling • cell spreading • lamellipodia • p38 mitogen-activated protein kinase • low density lipoprotein • lipoproteins • low density lipoprotein receptor • fibroblasts

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