Manganese superoxide dismutase (MnSOD) is the only antioxidant enzyme which is indispensable for the existence of higher eukaryotes. To gain better insight into the essential role of MnSOD, I developed a conditional transgenic mouse strain in which MnSOD expression was put under the control of the tetracycline regulatory system. The present work describes the generation of the transgenic mouse strain and characterizes consequences of MnSOD suppression for the physiology of the genetically altered animals. Furthermore, I describe the effects of MnSOD overexpression and deficiency in different cell culture systems. My results demonstrate that a two-fold higher activity of MnSOD had no influence on activities of other antioxidant enzymes, namely CuZnSOD, CAT and GPX. As expected, the increased level of MnSOD expression protected cells from death under hyperoxic conditions. It also prevented apoptosis induced by hydrogen peroxide administration. Unexpectedly, however, overexpression of MnSOD did slightly enhance doxorubicin-induced programmed cell death although I observed an almost complete inhibition of apoptosis induced by doxorubicin or hydrogen peroxide in primary fibroblasts isolated from MnSOD-/- mice. These results suggest an involvement of MnSOD in ceramide mediated apoptosis and in the regulation of the balance between nitric oxide and peroxynitrite. These findings represent a new aspect of the regulation of programmed cell death. I also detected that MnSOD deficient cells contained higher level of free radicals and were more susceptible to hyperoxia. Surprisingly, but in accordance with the proposed role of hydrogen peroxide in senescence, MnSOD-/- fibroblasts appeared to senesce slower than corresponding wild type cells. Taken together, the results of in vitro studies demonstrated a central role of MnSOD in the regulation of cellular oxidative stress and revealed that MnSOD is indispensable for the progression of apoptosis and senescence. In order to generate an animal model for the regulated expression of MnSOD four strains of transgenic mice were produced. Two of them showed a comparatively low expression of SOD and an ineffective regulation of SOD transcription. One of the remaining strains was used to study the effects of a partial and complete MnSOD deficiency in vivo (SOD/TRE) while the last strain allowed a regulated MnSOD expression in the heart (SOD/αMHC tTA). In the absence of an additional allele, which carries the tetracycline receptor to achieve tissue specific or ubiquitous expression of MnSOD, the SOD/TRE strain might be used as a constitutive knock-out model for SOD. In the presence of the tetracycline receptor, however, the expression of MnSOD can be reversibly switched on and off by administration of doxycycline in drinking water. Complete MnSOD deficiency in homozygous SOD/TRE mice led to early-onset lethality and to massive phenotypical changes as indicated by a reduced body size and weight together with neurological abnormalities. Strong up-regulation of ANF expression in hearts of 3 days old animals was observed. The same hearts showed a slightly increased rate of apoptosis, although TUNEL-positive cells were rare and accumulated only in the epicardium. Despite earlier description of phenotypical changes, my immunohistochemical stainings suggest that apoptosis in the hearts of MnSOD-/- mice is not the primary cause of cardiac failure. Heterozygous SOD/TRE mice showed a 30-40% reduced MnSOD activity in the heart, brain and liver. This attenuation of mitochondrial dismutase did not affect the activity of CuZnSOD, CAT or GPX. Interestingly, the 30% reduction of MnSOD activity in the hearts of 6 months old mice clearly reduced the cardiac performance of heterozygous mutant SOD mice. Left ventricle fraction shortening and fractional area change were decreased in these animals by 26% and 21%, respectively. Furthermore, treatment with doxorubicin, a cytotoxic drug which causes heart dilation, induced apoptosis in the hearts of SOD/TRE heterozygotes and stimulated expression of ANF. The first effect was confined to restricted areas of epicardium, the latter was detectable throughout the heart. Senescence-associated β-galactosidase staining revealed that endothelial and smooth muscle cells in vessels proximal to the heart were less resistant to the stress induced by doxorubicin and displayed a senescent phenotype. In contrast, the heart tissue itself showed no signs of senescence in heterozygous SOD/TRE or in wild type mice. Taken together, my results demonstrate for the first time that even a partial reduction of MnSOD activity might impair heart function and might contribute to vascular pathogenesis. SOD/αMHC tTA homozygous mice survived up to 14 days and showed the same phenotypical changes as homozygous SOD/TRE and knock-out mice, which have been constructed previously. I found that the transcription of the engineered SOD allele was readily regulated in vivo by administration of doxycycline in drinking water and gave rise to a transcript of the predicted size, which generated a protein of the expected molecular weight. Regulation was shown to be effective also at the protein level. Since transcription of the tetracycline receptor was driven by α-myosin heavy chain promoter, expression of the transgene was achieved exclusively in the heart thereby successfully establishing a mouse model with heart-specific regulated expression of MnSOD. In the presented work I described experiments performed in vivo and in vitro, which contribute to the understanding of the function of MnSOD in cellular and physiological processes. The SOD/TRE and SOD/αMHC tTA animal models generated in the course of this work will provide convenient research tools which might help to elucidate the role of MnSOD in many pathological processes in various tissues at different time points.