Anthracycline cardiotoxicity in transgenic mice overexpressing SR Ca2+-ATPase.
Chronic anthracycline administration results in a time- and dose-dependent cardiomyopathy. The Ca-ATPase of the sarcoplasmic reticulum, SERCA2, has been implicated as a principal target for anthracycline-induced cardiotoxicity. This hypothesis predicts that improved SERCA2 function would provide protection from cardiotoxic effects of anthracycline administration. Doxorubicin was administered (1.7 mg/kg three times weekly; cumulative dose of 20 mg/kg) to 10 transgenic mice that overexpressed SERCA2 and to 10 isogenic littermates. Survival was monitored for 60 days and histologic comparisons were made of cardiac tissue. Survival in the transgenic mice was worse (1/10 60-day survivors) compared to isogenic control mice (7/10 60-day survivors). There was a greater degree of histologic damage exhibited in hearts from transgenic mice compared to isogenic controls when all available hearts were examined. These data do not support a role of SERCA2 in ameliorating anthracycline cardiotoxicity.
Burke
Briant E
BE
Center for Biomedical Research, Boise, ID 83706, USA. drq10@iglide.net
Olson
Richard D
RD
Cusack
Barry J
BJ
Gambliel
Herve A
HA
Dillmann
Wolfgang H
WH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D000903:Antibiotics, Antineoplastic; C506948:Atp2a2 protein, rat; D007527:Isoenzymes; D011994:Recombinant Proteins; D004317:Doxorubicin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases