Targeted overexpression of ornithine decarboxylase enhances β-adrenergic agonist-induced cardiac hypertrophy

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Abstract

These studies were designed to determine the consequences of constitutive overexpression of ornithine decarboxylase (ODC) in the heart. Induction of ODC is known to occur in response to agents that induce cardiac hypertrophy. However, it is not known whether high ODC levels are sufficient for the development of a hypertrophic phenotype. Transgenic mice were generated with cardiac-specific expression of a stable ODC protein using the α-myosin heavy-chain promoter. Founder lines with > 1000-fold overexpression of ODC in the heart were established, resulting in a 50-fold overaccumulation of putrescine, 4-fold elevation in spermidine, a slight increase in spermine and accumulation of large amounts of cadaverine compared with littermate controls. Despite these significant alterations in polyalamines, myocardial hypertrophy, as measured by ratio of heart to body weight, did not develop, although atrial natriuretic factor RNA was slightly elevated in transgenic ventricles. However, stimulation of β-adrenergic signalling by isoproterenol resulted in severe hypertrophy and even death in ODC-overexpressing mice without further altering polyamine levels, compared with only a mild hypertrophy in littermates. When β1-adrenergic stimulation was blocked by simultaneous treatment with isoproterenol and the β1 antagonist atenolol, a significant, although reduced, hypertrophy was still present in the hearts of transgenic mice, suggesting that both β1 and β2 adrenergic receptors contribute to the hypertrophic phenotype. Therefore these mice provide a model to study the in vivo cooperativity between high ODC activity and activation of other pathways leading to hypertrophy in the heart.

Original languageEnglish (US)
Pages (from-to)25-32
Number of pages8
JournalBiochemical Journal
Volume358
Issue number1
DOIs
StatePublished - Aug 15 2001

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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