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 non-transgenic 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 48h. Myocytes isolated from transgenic mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca2+] 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 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.

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

“…We evaluated whether MAPKs were able to induce expression of ODC, the first and rate‐limiting enzyme in polyamine biosynthesis 18, 19. We found that CAP (2 μmol/L) was able to induce a significant increase in protein expression of ODC; however, in the presence of KN‐93 or the p38‐selective inhibitor BIRB‐796, the expression of ODC was greatly downregulated.…”

Endoplasmic Reticulum Stress is Involved in DFMO Attenuating Isoproterenol-Induced Cardiac Hypertrophy in Rats

“…Inhibition of polyamine uptake potentiates the anti-proliferative effect of polyamine synthesis inhibition and preserves [17]. Overexpression of ODC was found to decrease ventricular systolic function during cardiac hypertrophy through assessment of the left ventricular ejection fraction (LVEF) and shortening fraction (FS) by echocardiography [18]. Cardiac fibrosis was identified using Masson staining and TUNEL was also used to detect the apoptosis of the myocardium from ISO-treated mice.…”

Arginase inhibition attenuates arteriogenesis and interferes with M2 macrophage accumulation

“…The control group received saline only. L-Arginine was dissolved in drinking water (5%, w/v), [17][18][19] corresponding to a dose of about 330 mg per day per animal, and pH was adjusted to 7. L-Arginine supplementation was started 3 days before the surgical procedure and administered until the end of the experiment.…”