Doxorubicin cardiac dysfunction: effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine.
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) Ca2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [3H]-ryanodine binding (B(max)) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor alpha2 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.
Olson
Richard D
RD
Pharmacology and Gerontology Research Unit, Veteran's Affairs Medical Center, 500 W. Fort St., Boise, ID 83702, USA. rolson49@aol.com
Gambliel
Hervé A
HA
Vestal
Robert E
RE
Shadle
Susan E
SE
Charlier
Henry A
HA
Cusack
Barry J
BJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002155:Calsequestrin / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004562:Electrocardiography; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D023282:Nuclease Protection Assays; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*; D000099211:Phospholamban
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002155:Calsequestrin; D004317:Doxorubicin; D011506:Proteins; D012313:RNA; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D013972:Thyrotropin; D014284:Triiodothyronine; D000099211:Phospholamban