Cardiac remodeling i.e. the adaption of the heart to pathological changes is a critical factor for the development of heart failure. Transforming growth factor β (TGFβ) is up-regulated in the myocardium during transition from compensated hypertrophy to heart failure that is accompanied by apoptosis. This process is controlled by transcription factors like AP-1 and SMADs that are both involved in TGFβ₁- as well as NO-induced apoptosis. Despite a 300-fold increase of cardiac NO formation, TGiNOS mice with cardiac overexpression of inducible NO synthase showed no signs of heart failure. This mild phenotype is mostly due to myoglobin that scavenges free NO in the cell. Since earlier studies have shown that NO and TGFβ₁ induced the activation of SMAD transcription factors leading to apoptosis, we wanted to investigate how far this pathway is modulated in TGiNOS mice.

To answer this question we analysed TGFβ pathway in TGiNOS hearts and isolated cardiomyocytes. INOS-overexpressing hearts showed a decrease in cardiac TGFβ mRNA and protein expression. SMAD4 mRNA was significantly decreased in TG-iNOS mice hearts compared to WT controls. In contrast, inhibitory SMAD7 that is able to down-regulate the TGFβ pathway, was increased in TGiNOS hearts. When isolated TGiNOS- and wild type (WT) cardiomyocytes were incubated with a low dose (1ng/ml) of TGFβ1, only iNOS-overexpressing cardiomyocytes but not WT cells responded with apoptosis. Furthermore, analysis of contraction parameters after TGFβ1 incubation (1ng/ml), like cell shortening dL/L (%)contraction and relaxation velocity showed a considerably stronger reduction in iNOS-overexpressing cardiomyocytes than in WT cells. Conclusion: Down regulation of TGFβ signaling may represent an important mechanism to protect cardiomyocytes against the synergistic action of TGFβ and NO in the induction of apoptosis and preservation of contractile function.