Modulation of doxorubicin-induced cardiac dysfunction in dominant-negative p38α mitogen-activated protein kinase mice

被引:47
作者
Thandavarayan, Rajarajan A. [1 ,2 ]
Watanabe, Kenichi [1 ]
Sari, Flori R. [1 ]
Ma, Meilei [1 ]
Lakshmanan, Arun Prasath [1 ]
Giridharan, Vijayasree V. [2 ]
Gurusamy, Narasimman [3 ]
Nishida, Hiroshi [2 ]
Konishi, Tetsuya [2 ]
Zhang, Shaosong [4 ]
Muslin, Anthony J. [5 ]
Kodama, Makoto [6 ]
Aizawa, Yoshifusa [6 ]
机构
[1] Niigata Univ Pharm & Appl Life Sci, Dept Clin Pharmacol, Niigata 9568603, Japan
[2] Niigata Univ Pharm & Appl Life Sci, Dept Funct & Analyt Food Sci, Niigata 9568603, Japan
[3] Harvard Univ, Dept Anesthesiol & Med, Sch Med, Boston, MA 02115 USA
[4] Lightlab Imaging Inc, Westford, MA 01886 USA
[5] Washington Univ, Cardiovasc Res Ctr, Dept Internal Med, Sch Med, St Louis, MO 63110 USA
[6] Niigata Univ, Dept Med 1, Grad Sch Med & Dent Sci, Niigata, Japan
关键词
Doxorubicin; p38 alpha MAPK; Oxidative stress; Apoptosis; Free radicals; P38 MAP KINASE; LEFT-VENTRICULAR DYSFUNCTION; MUSCLE-CELL HYPERTROPHY; INDUCED CARDIOMYOPATHY; TRANSGENIC MICE; ANGIOTENSIN-II; INDUCED APOPTOSIS; OXIDATIVE STRESS; REACTIVE OXYGEN; NADPH OXIDASE;
D O I
10.1016/j.freeradbiomed.2010.08.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38 alpha mitogen-activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38 alpha MAPK is not clear in Dox-induced cardiac injury. Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) mice and transgenic mice with cardiac-specific expression of a dominant-negative mutant form of p38 alpha MAPK (TG). Left ventricular (LV) fractional shortening and ejection fraction were higher and the expression levels of phospho-p38 MAPK and phospho-MAPK-activated mitogen kinase 2 were significantly suppressed in TG mouse heart compared to WT mice after Dox injection. Production of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3-positive cells, and phospho-p53 expression were decreased in TG mice after Dox injection. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species was significantly less in TG mice compared to WT mice after Dox injection. These findings suggest that p38 alpha MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:1422 / 1431
页数:10
相关论文
共 56 条
[1]   Gamma ray induced DNA damage in human and mouse leucocytes measured by SCGE-Pro: a software developed for automated image analysis and data processing for Comet assay [J].
Chaubey, RC ;
Bhilwade, HN ;
Rajagopalan, R ;
Bannur, SV .
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 2001, 490 (02) :187-197
[2]  
Dowd NP, 2001, J CLIN INVEST, V108, P585, DOI 10.1172/JCI200111334
[3]   Growth factors and mitogen activated protein kinases [J].
Force, T ;
Bonventre, JV .
HYPERTENSION, 1998, 31 (01) :152-161
[4]   DOXORUBICIN TOXICITY IN PERFUSED RAT-HEART - DECREASED CELL-DEATH AT LOW OXYGEN-TENSION [J].
GANEY, PE ;
CARTER, LS ;
MUELLER, RA ;
THURMAN, RG .
CIRCULATION RESEARCH, 1991, 68 (06) :1610-1613
[5]   p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389 [J].
Huang, CS ;
Ma, WY ;
Maxiner, A ;
Sun, Y ;
Dong, ZG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (18) :12229-12235
[6]   Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase - Effect of antiapoptotic antioxidants and calcium [J].
Kalivendi, SV ;
Kotamraju, S ;
Zhao, H ;
Joseph, J ;
Kalyanaraman, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (50) :47266-47276
[7]   AN ELECTRON-SPIN RESONANCE STUDY OF THE REDUCTION OF PEROXIDES BY ANTHRACYCLINE SEMIQUINONES [J].
KALYANARAMAN, B ;
SEALY, RC ;
SINHA, BK .
BIOCHIMICA ET BIOPHYSICA ACTA, 1984, 799 (03) :270-275
[8]   Suppression of cardiotoxicity by overexpression of catalase in the heart of transgenic mice [J].
Kang, YJ ;
Chen, Y ;
Epstein, PN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12610-12616
[9]   Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity [J].
Kang, YJ ;
Chen, Y ;
Yu, AD ;
VossMcCowan, M ;
Epstein, PN .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (06) :1501-1506
[10]   Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms [J].
Kim, JK ;
Pedram, A ;
Razandi, M ;
Levin, ER .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (10) :6760-6767