Aims: 

There is upcoming evidence that the lack of an appropriate increase in eNOS activity by induction of eNOS expression induces disease stages under stress even though eNOS expression is sufficient under basal conditions. eNOS heterozygous mice (eNOS+/­) represent a suitable model to prove this finding. Recently it was shown that physical training is sufficient to induce a cardiac phenotype in eNOS+/­ mice. As this requires an activation of the sympathetic nervous system that activates ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine metabolism, we now challenged the hypothesis that ODC activation induces heart disease in eNOS+/­ mice due to the competition for arginine required for both pathways.

Methods: 

We investigated a total of 34 female eNOS+/­ mice. Creatinin serum level, heart weight to body weight ratio (HW/BW), and left ventricular expression of fibrotic, apoptotic, hypertrophic markers and calcium handling proteins (quantitative real-time RT-PCR) were determined at the age of 6 months.

Results: 

34 eNOS+/­ mice were analyzed in this study and subdivided into quartiles in order of their left ventricular ODC expression. ODC mRNA expression of the four groups were 0.67, 1.09, 1.60, and 2.05 arbitrary units (each p>0.05). As ODC is known to be regulated exclusively on the mRNA expression level this represents an activation of the polyamine metabolism. We found a positive correlation between the grade of illness (distress score ranking), and an inverse correlation to body weights. The group with the highest left ventricular ODC expression had the highest HW/BW ratio and the highest lung wet weight (both p<0.02 vs. the group with the lowest ODC expression). Positive correlation to ODC expression were also found for elastin, elastin-to-collagen-1 ratio, bax, ANF, and decorin. An inverse correlation was found for the bcl-2-to-bax ratio and NCX expression.

Conclusion: 

An activation of ODC competes with the NO pathway for arginine. An imbalance between these pathways favouring the polyamine metabolism induces the expression of pro-fibrotic, hypertrophic, and apoptotic pathways. In the absence of only one allele of eNOS this is sufficient to induces a moderate type of heart failure.