Anthracycline cardiotoxicity in transgenic mice overexpressing SR Ca2+-ATPase☆
Section snippets
Materials and methods
Construction of SERCA2 transgenic mice. Transgenic mice overexpressing SERCA2 were constructed and the transgenic mice were raised, bred, and maintained at the facilities of UC San Diego. The transgenic construct has been reported in detail previously [21]. Briefly, a rat SERCA2a transgene was cloned into the pBluescript SK plasmid (Strategene, La Jolla, CA) and the plasmid was then cleaved using SalI and BamHI to isolated the expression unit of the SERCA2 gene. The pronuclei of eggs from
Results
Fig. 1 shows the effect of doxorubicin treatment on survival of transgenic and isogenic control littermates. Cardiac SERCA2 overexpression conferred no survival advantage over isogenic controls. In fact, the mortality in the transgenic mice was significantly greater than the isogenic controls by day 45 (p<0.05; Fisher’s exact test).
Histopathologic scores for transgenic and isogenic control mice euthanized during the study due to a moribund condition (i.e., near death) did not differ
Discussion
Various hypotheses to explain the mechanism(s) of chronic anthracycline cardiotoxicity have been proposed [3], [4]. These include mitochondrial dysfunction [23], [24], disruption of calcium homeostasis [5], [6], [7], [11], [25], free-radical mediated damage [3], [26], membrane pump dysfunction [24], [27], or effects on the contractile apparatus [9]. Recent evidence indicates that chronic doxorubicin treatment causes an impairment of sarcoplasmic reticulum function [5], [6], [7], [8], with
Acknowledgements
We gratefully acknowledge Troy Scott of the animal facilities at UCSD for his able assistance. This work was supported by the Department of Veteran’s Affairs and the MSTI/MSMRI Research Institute, Boise ID, and NHLBI Grant R37-HL-49424 to WH Dillmann.
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This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.