© 2000 American Heart Association, Inc.
Vascular Biology |
Hyperexpression and Activation of Extracellular Signal–Regulated Kinases (ERK1/2) in Atherosclerotic Lesions of Cholesterol-Fed Rabbits
From the Institute for General and Experimental Pathology (Y.H., H.D., G.W.) and Division of Cardiology, Department of Internal Medicine (B.M.), University of Innsbruck Medical School, and the Institute for Biomedical Aging Research (G.W., Q.X.), Austrian Academy of Sciences, Innsbruck, Austria.
Correspondence to Dr Qingbo Xu, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail qingbo.xu{at}oeaw.ac.at
Abstract—A hallmark of
hyperlipidemia-induced atherosclerosis
is altered gene expression that initiates cell proliferation and
(de)differentiation in the intima of the arterial wall. The
molecular signaling that mediates this process in vivo has yet to be
identified. Extracellular signal–regulated kinases (ERKs) are thought
to play a pivotal role in transmitting transmembrane signals required
for cell proliferation in vitro. The present studies were designed
to investigate the activity, abundance, and localization of ERK1/2 in
atherosclerotic lesions of cholesterol-fed rabbits.
Immunofluorescence analysis revealed
abundant and heterogeneous distribution of ERK1/2, mainly
localized in the cap and basal regions of atheromas. A
population of ERK-enriched cells was identified as 
-actin–positive
smooth muscle cells (SMCs). ERK1 and 2 were heavily
phosphorylated on tyrosyl residues and coexpressed with
proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2
protein levels in protein extracts from atherosclerotic lesions were 2-
to 3-fold higher than the vessels of chow-fed rabbits, and their
activities were elevated 3- to 5-fold over those of the normal vessel.
SMCs derived from atherosclerotic lesions had increased
migratory/proliferative ability and higher ERK activity in response to
LDL stimulation compared with cells from the normal vessel. Inhibition
of ERK activation by PD98059, a specific inhibitor of
mitogen-activated protein kinase kinases (MEK1/2), abrogated
LDL-induced SMC proliferation in vitro. Taken together, our findings
support the proposition that persistent activation and hyperexpression
of ERK1/2 may be a critical element to initiate and perpetuate cell
proliferation during the development of atherosclerosis.
Key Words: atherosclerosis • animal models • MAP kinases • ERK • signal transduction
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