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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 1, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn335
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Oxidative stress and left ventricular remodeling after myocardial infarction

Masatsugu Hori1,* and Kazuhiko Nishida2

1 Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
2 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan

* Corresponding author: Masatsugu Hori Tel: +81-6-6972-1181; Fax: +81-6-6981-7050; E-mail address: hori-ma{at}mc.pref.osaka.jp

In acute myocardial infarction (MI), reactive oxygen species (ROS) are generated in the ischemic myocardium especially after reperfusion. ROS directly injure the cell membrane and cause cell death. However, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1β and -6, in the ischemic region and surrounding myocardium as a host reaction. Inflammatory cytokines also regulate cell survival and cell death in the chain reaction with ROS. Both ROS and inflammatory cytokines are cardiodepressant mainly due to impairment of intracellular Ca2+ homeostasis. Inflammatory cytokines stimulate apoptosis through a TNF-{alpha} receptor/caspase pathway, whereas Ca2+ overload induced by extensive ROS generation causes necrosis through enhanced permeability of the mitochondrial membrane (mitochondrial permeability transition). Apoptosis signal regulating kinase-1 (ASK1) is an ROS-sensitive, mitogen-activated protein kinase kinase kinase that is activated by many stress signals and can activate nuclear factor {kappa}B and other transcription factors. ASK1-deficient mice demonstrate that the ROS/ASK1 pathway is involved in necrotic as well as apoptotic cell death, indicating that ASK1 may be a therapeutic target to reduce left ventricular (LV) remodeling after MI. ROS and inflammatory cytokines activate matrix metalloproteinases which degrade extracellular matrix, causing a slippage of myofibrils and hence LV dilatation. Consequently, collagen deposition is increased and tissue repair is enhanced with myocardial fibrosis and angiogenesis. Since the extent of LV remodeling is a major predictor of prognosis of the patients with MI, the therapeutic approach to attenuating LV remodeling is critically important.

KEYWORDS Oxidative stress; Reactive oxygen species; Inflammatory cytokine; Remodeling; Myocardial infarction

Time for primary review: 24 Days


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