TGFb is expressed in the myocardium during the transition from adopted hypertrophic growth to heart failure. In cardiomyocytes of adult rat (CM) stimulation with TGFb results in restricted cardiac function and apoptosis. Both processes are fundamental for the development of heart failure. Besides TGFb nitric oxide (NO) induces apoptosis and both molecules act via the transcription factor (TF) SMAD. The question arises whether NO plays a role as a signal molecule in TGFb induced apoptosis. Therefore we performed studies on isolated CM of rat under apoptosis inducing conditions with TGFb1 (1ng/ml) and measured the formation of NO. The NO release increased and could be inhibited with the NO-synthase inhibitor ETU (10 mM). TGFb stimulation results in activation of SMAD TFs. The TGFb?induced increase in SMAD binding activity could be reduced when cells were pre-incubated with ETU. Incubation of CM with TGFb enlarged the number of apoptotic cells. Apoptosis induction can be abolished when CM were incubated with ETU. To examine the function of the cells, CM were stimulated with 2

Hz and cell shortening [dL/L %]was detected. TGFb reduced [dL/L %] but when CM were stimulated in presence of ETU [dL/L %] did not change.

Conclusion: TGFb induces the formation of NO. The use of the NOS inhibitor ETU reduces the TGFb induced SMAD activation, apoptosis-induction and normalise cardio depression. NO plays therefore a role as a further signal molecule in TGFb mediated apoptosis.