title: 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.affiliation: Department of Cellular & Molecular Physiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.|Dipartimento di Biochimica "G. Moruzzi", Università di Bologna, 40126 Bologna, Italia.|National Institute for Cardiovascular Research (INRC), Bologna, 40126 Bologna, Italia.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Giordano
authors.affiliation: Department of Cellular & Molecular Physiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Hillary
authors.affiliation: Department of Cellular & Molecular Physiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Vary
authors.affiliation: Department of Cellular & Molecular Physiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pegg
authors.affiliation: Department of Cardiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Sumner
authors.affiliation: National Institute for Cardiovascular Research (INRC), Bologna, 40126 Bologna, Italia.
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Caldarera
authors.affiliation: Division of Nephrology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Xue-Qian
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Song
authors.affiliation: Division of Nephrology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: JuFang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Department of Cellular & Molecular Physiology, The Penn State College of Medicine; Hershey, PA 17033-2390, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shantz
mesh_terms: D000200:Action Potentials; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D002851:Chromatography, High Pressure Liquid; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D013599:Systole
chemical_list: D009955:Ornithine Decarboxylase; D007545:Isoproterenol