title: Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5344, USA.
authors.forename: Asimina
authors.initials: A
authors.lastname: Hiona
authors.forename: Andrew Stephen
authors.initials: AS
authors.lastname: Lee
authors.forename: Jayan
authors.initials: J
authors.lastname: Nagendran
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xie
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy*; D053148:Caspase 3 / Q000032:analysis; D053453:Caspase 9 / Q000032:analysis; D004317:Doxorubicin / Q000009:adverse effects*; D004656:Enalapril / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D005609:Free Radicals; D004656:Enalapril; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053453:Caspase 9