Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function

Asimina Hiona, Andrew Stephen Lee, Jayan Nagendran, Xiaoyan Xie, Andrew J. Connolly, Robert C. Robbins, Joseph C. Wu

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Objective: Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline-induced heart failure. This study evaluated a mechanism for these protective effects by testing the ability of the angiotensin-converting enzyme inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats. Methods: Sprague Dawley rats were divided into 3 groups and followed for a total of 10 weeks: (1) control-untreated, (2) doxorubicin treated, and (3) doxorubicin + enalapril treated. Doxorubicin was administered via intraperitoneal injection at weekly intervals from weeks 2 to 7. Enalapril was administered in the drinking water of the doxorubicin + enalapril group for the study duration. Results: Doxorubicin treatment produced a significant loss in left ventricular contractility (P < .05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of adenosine triphosphate, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P <.05) and prevented the doxorubicin- associated reduction in respiratory efficiency and cytosolic adenosine triphosphate content (P <.05). Enalapril also abolished the robust doxorubicin-induced increase in free radical formation. Conclusions: Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.

Original languageEnglish (US)
Pages (from-to)396
Number of pages1
JournalJournal of Thoracic and Cardiovascular Surgery
Volume142
Issue number2
DOIs
StatePublished - Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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