title: Mechanical unloading improves intracellular Ca2+ regulation in rats with doxorubicin-induced cardiomyopathy.
abstract: OBJECTIVE
  We sought to assess whether mechanical unloading has beneficial effects on cardiomyocytes from doxorubicin-induced cardiomyopathy in rats.
  
  
  BACKGROUND
  Mechanical unloading by a left ventricular assist device (LVAD) improves the cardiac function of terminal heart failure in humans. However, previous animal studies have failed to demonstrate beneficial effects of mechanical unloading in the myocardium.
  
  
  METHODS
  The effects of mechanical unloading by heterotopic abdominal heart transplantation were evaluated in the myocardium from doxorubicin-treated rats by analyzing the intracellular free calcium level ([Ca(2+)](i)) and the levels of intracellular Ca(2+)-regulatory proteins.
  
  
  RESULTS
  In doxorubicin-treated rats, the duration of cell shortening and [Ca(2+)](i) transients in cardiomyocytes was prolonged (432 +/- 28.2% of control in 50% relaxation time; 184 +/- 10.5% of control in [Ca(2+)](i) 50% decay time). Such prolonged time courses significantly recovered after mechanical unloading (114 +/- 10.4% of control in 50% relaxation time; 114 +/- 5.8% of control in 50% decay time). These effects were accompanied by an increase in sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) protein levels (0.97 +/- 0.05 in unloaded hearts vs. 0.41+/- 0.09 in non-unloaded hearts). The levels of other intracellular Ca(2+)-regulatory proteins (phospholamban and ryanodine receptor) were not altered after mechanical unloading in doxorubicin-treated hearts. These parameters in unloaded hearts without doxorubicin treatment were similar to normal hearts.
  
  
  CONCLUSIONS
  Mechanical unloading increases functional sarcoplasmic reticulum Ca(2+) ATPase and improves [Ca(2+)](i) handling and contractility in rats with doxorubicin-induced cardiomyopathy. These beneficial effects of mechanical unloading were not observed in normal hearts.
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan. takeseya@med.kurume-u.ac.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Takaseya
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishimatsu
authors.forename: Eiki
authors.initials: E
authors.lastname: Tayama
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasu
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Aoyagi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D002118:Calcium / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000502:physiology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology*; D004317:Doxorubicin; D016027:Heart Transplantation / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D000903:Antibiotics, Antineoplastic; D019837:Ryanodine Receptor Calcium Release Channel; D004317:Doxorubicin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium