Publication: Critical and diverse in vivo roles of apoptosis
signal-regulating kinase 1 in animal models
of atherosclerosis and cholestatic liver injury
Authors
Yamada, Sohsuke ; Noguchi, Hirotsugu ; Tanimoto, Akihide
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Publisher
Universidad de Murcia. Departamento de Biología Celular e Histología
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DOI
DOI: 10.14670/HH-11-840
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info:eu-repo/semantics/article
Description
Abstract
. Apoptosis plays pivotal in vivo roles in not
only vital processes, such as cell turnover and embryonic
development, but also various inflammatory disorders.
However, the role of apoptosis by vascular and hepatic
cells in the respective progression of atherosclerosis and
liver injury remains controversial. Apoptosis signalregulating kinase 1 (ASK1) is a mitogen-activated
protein kinase kinase kinase family member that is
activated through distinct mechanisms in response to
various cytotoxic stressors. ASK1, ubiquitously
expressed, is situated in an important upstream position
for many signal transduction pathways, which
subsequently induce inflammation and/or apoptosis. Our
serial in vivo studies have uniquely reported that the
expression of phosphorylated ASK1 is variably seen in
atherosclerotic lesions or bile-duct-ligation (BDL)-
induced injury livers. In mice genetically deficient of
ASK1 (ASK1-/-
), activated ASK1 signaling accelerates
high-cholesterol-diet-induced necrotic lipid core
formation by inducing macrophage apoptosis and
enhances ligation injury-induced vascular remodeling
via pro-inflammatory reactions and by stimulating
apoptosis of smooth muscle cells. In contrast, in models
of BDL-induced cholestatic liver injury, the pathogenic
roles of ASK1-mediated early necro-inflammation, but
not apoptosis, and the proliferation of hepatocytes and
cholangiocytes are crucial in subsequent peribiliary
fibrosis/fibrogenesis. These animal models of acute to
chronic inflammatory diseases show that stimulated
ASK1 signaling critically and diversely regulates not
only hypercholesterolemia-induced atherosclerosis and
injury-induced arteriosclerosis, but also the acute and
subacute-to-chronic phase of BDL-induced cholestasis.
We herein review the diverse, key in vivo roles of ASK1
signaling in the pathogenesis of inflammatory disorders
closely related to metabolic syndrome.
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Citation
Histology and Histopathology, Vol.32, nº5, (2017)
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