Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity

Masashi Yoshida, Ichiro Shiojima, Hiroyuki Ikeda, Issei Komuro

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage, ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.

Original languageEnglish
Pages (from-to)698-705
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume47
Issue number5
DOIs
Publication statusPublished - Nov 1 2009
Externally publishedYes

Fingerprint

Doxorubicin
DNA Damage
Apoptosis
Oxidative Stress
Muscle Cells
pitavastatin
Cardiotoxicity
Tumor Suppressor Protein p53
Mevalonic Acid
Free Radical Scavengers
Cardiac Myocytes
Transgenic Mice
Phosphotransferases
Antioxidants

Keywords

  • Apoptosis
  • Cardiomyopathy
  • Doxorubicin
  • p53
  • Statins

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. / Yoshida, Masashi; Shiojima, Ichiro; Ikeda, Hiroyuki; Komuro, Issei.

In: Journal of Molecular and Cellular Cardiology, Vol. 47, No. 5, 01.11.2009, p. 698-705.

Research output: Contribution to journalArticle

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