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Small Heat Shock Proteins and Doxorubicin-Induced Oxidative Stress in the Heart

  • Karthikeyan Krishnamurthy
  • Ragu Kanagasabai
  • Lawrence J. Druhan
  • Govindasamy IlangovanEmail author
Chapter
  • 1.1k Downloads
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)

Abstract

Doxorubicin (Dox) and its derivatives are used as chemotherapeutics, either alone or in combination with other agents. Dilated cardiomyopathy and congestive heart failure due to cardiotoxicity continues to be the most serious side effect, imposing severe limitations in the use of these agents despite the arrival of new classes of Dox-derivatives and new formulations. In this chapter we summarize the recent understanding of the mechanism of Dox-induced cardiotoxicity and its relevance to the stress-inducible proteins, with special emphasis on the small heat shock proteins such as Hsp27, Hsp20, etc. The heat shock proteins are expressed as a response to the oxidative stress in the heart due to the redox reactions of these drugs and the generation of reactive oxygen species (ROS). On the other hand, ROS are also known to induce various MAP kinases and phosphorylate and activate the stress-responding transcription factors, including the heat shock factors (HSF). Activation of HSF-1 leads to the induction of a series of heat shock proteins, depending upon the type of exerted stress. Recent studies have confirmed that Dox-induced oxidative stress indeed leads to HSF-1 activation to induction of heat shock proteins, especially small Hsps in the heart. The Dox-induced small Hsps have been found to be involved in cell signaling and can be either cardioprotective or detrimental. Additionally, a few transgenic animal models have shown that selective overexpression of these proteins can be cardioprotective against Dox. These results establish the fact that proper regulation of the function of small Hsps could eliminate cardiotoxicity and serve as a potential therapeutic target to protect the heart from Dox-induced toxicity.

Keywords

Adriamycin Doxorubicin Heart failure Heat shock factor-1 Oxidative stress Small heat shock proteins 

Notes

Acknowledgment

The studies that are summarized in this chapter, were supported by NIH grants R01HL078796, R21EB004658, R21HL094881 (to G.I.).

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Karthikeyan Krishnamurthy
  • Ragu Kanagasabai
  • Lawrence J. Druhan
  • Govindasamy Ilangovan
    • 1
    Email author
  1. 1.Division of Cardiovascular Medicine, Davis Heart and Lung Research InstituteOhio State UniversityColumbusUSA

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