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From the Division of Cardiology,*
Department of Internal Medicine,
and the Institute for General and Experimental
Pathology,
University of Innsbruck Medical
School; and the Institute for Biomedical Aging
Research,
Austrian Academy of Sciences,
Innsbruck, Austria
Hyperlipidemia alters gene expression of arterial endothelial and
smooth muscle cells (SMCs) and induces atherosclerotic lesions,
in which cell proliferation and apoptosis co-exist. The signal
transduction pathways that mediate these responses in the vessel wall
in vivo have yet to be identified. Stress-activated
protein kinases (SAPKs) or c-Jun NH2-terminal
protein kinases (JNKs) are thought to be crucial in transmitting
transmembrane signals required for cell differentiation and apoptosis
in vitro. In the present study, we investigated
the localization and activity of SAPK/JNK in atherosclerotic lesions of
cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant
and heterogeneous distribution of pan-SAPK/JNK and phosphorylated
SAPK/JNK, which were mainly localized in cell nuclei of the
lesional cap and basal regions. Double staining of the lesions
demonstrated that a portion of 
-actin+ SMCs and
RAM11+ macrophages contained abundant phosphorylated
SAPK/JNK proteins. SAPK/JNK protein levels in protein extracts from
atherosclerotic lesions were two- to threefold higher than the vessels
of chow-fed rabbits. SAPK/JNK activities were elevated three- to
fivefold higher than the normal vessels. Interestingly,
increased SAPK/JNK in lesions was co-localized or coincided with high
levels of transcription factor p53 as identified by double labeling and
immunoprecipitation. Abundant pro-apoptotic protein BAX and
BCL-XS were also observed. Furthermore, low-density
lipoprotein (LDL) and oxidized LDL stimulated SAPK/JNK activation in
cultured SMCs in a time- and dose-dependent manner. LDL also induced
SAPK/JNK activation in vascular SMCs derived from
LDL-receptor-deficient Watanabe rabbits, indicating a
LDL-receptor-independent process. Thus, SAPK/JNK persistently
hyperexpressed and activated in lesions may play a key role in
mediating cell differentiation and apoptosis during the development of
atherosclerosis via activation of transcription factor
p53.
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