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Anthracycline cardiotoxicity in transgenic mice overexpressing SR Ca2+-ATPase
Briant E Burke1, Richard D Olson, Barry J Cusack
1Center for Biomedical Research, Boise, ID 83706, USA. drq10@iglide.net
Abstract:
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.
Insights
Overexpressing SERCA2 in mice worsened outcomes from doxorubicin treatment, contrary to expectations. This study suggests SERCA2 does not protect against anthracycline cardiotoxicity.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Chronic anthracycline administration causes dose-dependent cardiomyopathy.
- Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) is a potential target in anthracycline cardiotoxicity.
Purpose of the Study:
- To investigate if enhanced SERCA2 function protects against anthracycline-induced cardiotoxicity.
- To evaluate the role of SERCA2 in doxorubicin cardiotoxicity.
Main Methods:
- Transgenic mice overexpressing SERCA2 and isogenic littermates received doxorubicin.
- Survival was monitored for 60 days.
- Cardiac tissue histology was compared between groups.
Main Results:
- Survival was significantly lower in SERCA2-overexpressing mice (1/10) compared to controls (7/10).
- Histologic examination revealed greater cardiac damage in transgenic mice.
Conclusions:
- Overexpression of SERCA2 did not ameliorate doxorubicin cardiotoxicity.
- These findings do not support a protective role for SERCA2 in anthracycline cardiotoxicity.