TY - JOUR
T1 - Doxorubicin cardiac dysfunction
T2 - Effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine
AU - Olson, Richard D.
AU - Gambliel, Hervé A.
AU - Vestal, Robert E.
AU - Shadle, Susan E.
AU - Charlier, Henry A.
AU - Cusack, Barry J.
PY - 2005/9
Y1 - 2005/9
N2 - Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca 2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [ 3H]-ryanodine binding (Bmax) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor α2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.
AB - Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca 2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [ 3H]-ryanodine binding (Bmax) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor α2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.
KW - Calcium
KW - Cardiotoxicity
KW - Doxorubicin
KW - Echocardiography
KW - Rested contractions
KW - Triiodothyronine
UR - http://www.scopus.com/inward/record.url?scp=27144443115&partnerID=8YFLogxK
U2 - 10.1385/CT:5:3:269
DO - 10.1385/CT:5:3:269
M3 - Article
C2 - 16244372
AN - SCOPUS:27144443115
SN - 1530-7905
VL - 5
SP - 269
EP - 283
JO - Cardiovascular Toxicology
JF - Cardiovascular Toxicology
IS - 3
ER -