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

Rajarajan A. Thandavarayan, Kenichi Watanabe, Flori R. Sari, Meilei Ma, Arun Prasath Lakshmanan, Vijayasree V. Giridharan, Narasimman Gurusamy, Hiroshi Nishida, Tetsuya Konishi, Shaosong Zhang, Anthony J. Muslin, Makoto Kodama, Yoshifusa Aizawa

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38α mitogen-activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38α 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 p38α 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 p38α MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration.

Original languageEnglish (US)
Pages (from-to)1422-1431
Number of pages10
JournalFree Radical Biology and Medicine
Volume49
Issue number9
DOIs
StatePublished - Nov 2010

Keywords

  • Apoptosis
  • Doxorubicin
  • Free radicals
  • Oxidative stress
  • P38α MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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