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 6 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. After breeding with mice carrying the tetracycline receptor, compound mice express MnSOD depending on the presence of tetracycline. Without tetracycline receptor the MnSOD gene is fully inactivated, and animals show an 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.
Conclusion: Our study demonstrates that lifelong 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 defence system.