Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits

J Mol Cell Cardiol. 1998 Feb;30(2):243-54. doi: 10.1006/jmcc.1997.0588.


The clinical utility of doxorubicin, an antineoplastic agent, is limited by its cardiotoxicity. Our objective was to determine whether expression of genes encoding proteins that affect Ca2+ homeostasis were altered in the hearts of rabbits chronically treated with doxorubicin. Twelve male New Zealand white rabbits received an injection of doxorubicin (2.5 mg/kg i.v.) once a week for 8 weeks. Eight rabbits were similarly injected with saline as controls. The cardiac function of both groups was evaluated 8 weeks after the final injection, as were the levels of expression of mRNA for Ca2+ transport proteins in the sarcoplasmic reticulum and plasma membrane. The amount of the sarcoplasmic reticulum Ca2+-ATPase and the Ca2+ uptake capacity of the protein were also quantitated. Cardiac output was significantly decreased in the doxorubicin-treated group (71+/-21 ml/min, P<0.05) compared with the control group (118+/-15 ml/min). The mRNA levels for the sarcoplasmic reticulum proteins were significantly diminished in the doxorubicin-treated hearts: ryanodine receptor-2 (relative expression level compared with controls, 0.35+/-0.13, P<0.01), sarcoplasmic reticulum Ca2+-ATPase (0.56+/-0.13, P<0.01), phospholamban (0.62+/-0.20, P<0.01) and cardiac calsequestrin (0. 57+/-0.26, P<0.01). In addition, both relative amount of sarcoplasmic reticulum Ca2+-ATPase protein (doxorubicin-treated group, 69+/-17% of control, P<0.01) and the Ca2+ uptake capacity (46. 9+/-9.8 nmol Ca2+/mg protein-5 min in doxorubicin group v 63.2+/-10. 4 in the control group, P<0.01) were concomitantly decreased with its mRNA expression level. Conversely, the mRNA levels for the plasma membrane proteins did not differ from those of control rabbits: the dihydropyridine receptor (relative expression level, 1. 03+/-0.30, N.S.), plasma membrane Ca2+-ATPase (0.93+/-0.33, N.S.) and the Na+/Ca2+ exchanger (0.87+/-0.34, N.S.). These findings suggest that a selective decrease in mRNA expression for sarcoplasmic reticulum Ca2+ transport proteins is responsible for the impaired Ca2+ handling, and thus, for the reduced cardiac function seen in the cardiomyopathy induced in rabbits by the long-term treatment with doxorubicin.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity*
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Channels, L-Type
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism
  • Cardiomyopathies / chemically induced*
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / physiopathology
  • Cell Membrane / drug effects
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Down-Regulation / drug effects
  • Doxorubicin / toxicity*
  • Heart / drug effects
  • Ion Transport / drug effects
  • Male
  • Myocardium / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rabbits
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / genetics*
  • Sarcoplasmic Reticulum / metabolism
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism


  • Antibiotics, Antineoplastic
  • Calcium Channels
  • Calcium Channels, L-Type
  • RNA, Messenger
  • Sodium-Calcium Exchanger
  • Doxorubicin
  • Calcium-Transporting ATPases
  • Calcium