Overproduction of cardiac S-adenosylmethionine decarboxylase in transgenic mice

The present study was designed to provide a better understanding of the role played by AdoMetDC (S-adenosylmethionine decarboxylase), the key rate-control ling enzyme in the synthesis of spermidine and spermine, in controlling polyamine levels and the importance of polyamines in cardiac physiology. The alpha MHC (alpha-myosin heavy chain) promoter was used to generate transgenic mice with cardiac-specific expression of AdoMetDC. A founder line (alpha MHC/AdoMetDC) was established with a > 100-fold increase in AdoMetDC activity in the heart. Transgene expression was maximal by 1 week of age and remained constant into adulthood. However, the changes in polyamine levels were most pronounced during the first week of age, with a 2-fold decrease in putrescine and spermidine and a 2-fold increase in spermine. At later times, spen-nine returned to near control levels, whereas putrescine and spermidine levels remained lower, suggesting that compensatory mechanisms exist to limit spermine accumulation. The alpha MHC/AdoMetDC mice did not display an overt cardiac phenotype, but there was an increased cardiac hypertrophy after beta-adrenergic stimulation with isoprenaline ('isoproterenol'), as well as a small increase in spermine content. Crosses of the alpha MHC/AdoMetDC with alpha MHC/ornithine decarboxylase mice that have a > 1000-fold increase in cardiac ornithine decarboxylase were lethal in utero, presumably due to increase in spermine to toxic levels. These findings suggest that cardiac spermine levels are highly regulated to avoid polyamine-induced toxicity and that homoeostatic mechanisms can maintain non-toxic levels even when one enzyme of the biosynthetic pathway is greatly elevated but are unable to do so when two biosynthetic enzymes are increased.