Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy.

Abstract

Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to β-adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC-ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl-isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to β-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility.

• Authors: Emanuele Giordano, Rebecca A Hillary, Thomas C Vary, Anthony E Pegg, Andrew D Sumner, Claudio M Caldarera, Xue-Qian Zhang, Jianliang Song, JuFang Wang, Joseph Y Cheung, Lisa M Shantz
• Journal: Amino acids (Amino Acids) Vol. 42 Issue 2-3 Pg. 507-518 (Feb 2012) ISSN: 1438-2199 [Electronic] Austria
• PMID: 21814794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ornithine Decarboxylase
• Isoproterenol

Topics

• Action Potentials
• Animals
• Cardiomegaly (chemically induced, enzymology, physiopathology)
• Chromatography, High Pressure Liquid
• Heart Ventricles (enzymology, physiopathology)
• Isoproterenol (pharmacology)
• Mice
• Mice, Transgenic
• Ornithine Decarboxylase (metabolism)
• Systole