Abstract 1172: Inducible and Cardiac Specific Overexpression of the Neuronal NO Synthase (nNOS or NOS1) Enzyme in a New Transgenic Mouse Model
The role of the neuronal NO synthase (nNOS or NOS I) enzyme in the control of cardiac function remains still unclear. Results from nNOS − /− mice are contradictory. We hypothesize that nNOS decreases myocardial contractility by affecting myocardial Ca2+ balance. To test this hypothesis a new transgenic mouse model with an inducible, myocardial nNOS overexpression was established in our working group. For generation of this transgenic animal model the Tet-Off system was used. Western blot analysis of mice transgene nNOS overexpression showed a 6-fold increase in nNOS protein expression compared to non-induced littermates (n = 12; p < 0.01). Measuring of total NOS activity by the conversion of [3H]-L-arginine to [3H]-L-citrulline showed a 27.3 ± 9.9% increase in the nNOS overexpressing mice (n = 5; p < 0.05). The phenotype of the nNOS overexpressing mice is heart failure already 2 weeks after induction. The heart-/bodyweight ratio was increased significantly (56.6 ± 5.3%; n = 11; p < 0.05). In vivo examinations of the induced mice showed a 28 ± 9% decrease of dp/dtmax compared to non-induced mice. Likewise, the ejection fraction was reduced significantly (56 ± 4.8% vs. 38 ± 6.1%; n = 15; p < 0.05). However, in isolated adult cardiomyocytes, the force-frequency relationship, relaxation time and SR Ca2+ content did not differ in nNOS overexpressing mice vs. non-induced littermates. Interestingly, co-immunprecipitation experiments indicated a co-localization of nNOS and L-type calcium channel. In conclusion, myocardial overexpression of nNOS in a transgene animal model caused heart failure. In contrast to other groups we could not observe any influence of nNOS on the SR Ca2+ content. We suggest that nNOS might have an impact on the L-type calcium channel.