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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 17, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp092
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Different extent of cardiac malfunction and resistance to oxidative stress in heterozygous and homozygous MnSOD-mutant mice

Tomasz Locha,b, Olesya Vakhrushevac, Izabella Piotrowskaa,c, Wieslaw Ziolkowskid, Henning Ebelta, Thomas Braunc and Eva Boberc,*

a Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Hollystr. 1, D-06097 Halle, Germany
b Department of Biotechnology and Genetic Engineering, Medical University of Silesia, Narcyzow 1, PL-41-200 Sosnowiec, Poland
c Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodelling, Parkstr. 1, D-61231 Bad Nauheim, Germany
d Department of Biochemistry, J. Sniadecki Academy of Physical Education and Sport, Gorskiego 1, PL-80-336 Gdansk and Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, Debinki 1, PL-80-211 Gdansk, Poland

* Corresponding author Tel.: +49-(0)6032-705271, FAX: +49-(0)6032-705419, E-mail: eva.bober{at}mpi-bn.mpg.de

Aims: The mitochondrially expressed manganese-dependent superoxide dismutase (MnSOD, SOD2) is an essential antioxidative enzyme that is necessary for normal heart function. In this study we investigated the heart function of mice that were exposed to increased oxidative stress for time periods of up to six months due to decreased MnSOD activity caused by heterozygous deletion of the MnSOD gene.

Methods and results: We generated a mouse strain in which the gene encoding MnSOD was exchanged against a cassette containing the SOD cDNA under the control of the tetracycline response element (TRE). After breeding with mice carrying the tetracycline receptor (TR), compound mice express MnSOD depending on the presence of tetracycline. Without TR the MnSOD gene is fully inactivated and animals show a MnSOD-deficient phenotype. Using echocardiographic recordings we found an impairment of left ventricular functions: MnSOD+/- mice displayed a decrease in fraction shortening and ejection fraction and an increase in left ventricular internal diameter in systole. Furthermore, MnSOD+/- mice developed heart hypertrophy with accompanying fibrosis and necrosis revealed by immunhistochemical analysis. Although we did not find an increase in apoptosis in MnSOD+/- hearts under normal conditions, we observed an increase of the number of apoptotic cells and vascular senescence after treatment with doxorubicin.

Conclusions: Our study demonstrates that life-long reduction of MnSOD activity has a negative effect on normal heart function. This animal model presents a valuable tool to investigate the mechanism of heart pathology reported in patients bearing different polymorphic variants of the MnSOD gene and to develop new therapeutic strategies through manipulation of the antioxidative defense system.

KEYWORDS apoptosis; fibrosis; heart failure; oxygen radicals; ventricular function

Time for primary review: 36 days


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