Attenuation of Isoproterenol-mediated Myocardial Injury in Rat by an Inhibitor of Polyamine Synthesis

Tipnis, Ulka R.; He, G.-Y; Li, Suzhen; Campbell, Gerald A.; Boor, Paul J.

doi:10.1016/s1054-8807(00)00038-7

Cited by 25 publications

(19 citation statements)

References 46 publications

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“…Our results have demonstrated that DFMO may play an anti-hypertrophic and anti-apoptotic role by inhibiting polyamine biosynthesis. These results are consistent with recent papers reporting a similar protective effect of DFMO against apoptosis in cardiac cells treated with aldosterone, or when cells were exposed to simulated ischemia conditions [20,21]. A study investigating the effects of polyamine depletion on norepinephrine mediated apoptosis in rat neonatal cardiomyocytes and H 9 C 2 cardiomyoblasts demonstrated that DFMO had a pro-survival effect that was mediated through a specific network of phosphatases and kinases [22].…”

Section: Discussionsupporting

confidence: 91%

“…Several recent studies have demonstrated that growth responses in cardiac tissue are accompanied by increased polyamine levels. In addition, DFMO, an irreversible inhibitor of ODC, can reduce putrescine levels by inhibiting the activity of ODC; it has also been shown to inhibit hypertrophy and fibrosis-related genic responses in cardiac cells [19,20,21]. In this study, we observed that ISO increased cardiac hypertrophy and the rate of apoptosis, and DFMO pretreatment attenuated hypertrophy and apoptosis in cardiomyocytes Furthermore, gene and protein levels of ODC and SSAT were increased in the ISO treated group.…”

Section: Discussionmentioning

confidence: 99%

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Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

Yan

Zhang

Wang

et al. 2014

Cell Physiol Biochem

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Background/Aim: Polyamines (putrescine, spermidine and spermine) play an essential role in cell growth, differentiation and apoptosis. Hypertrophy is accompanied by an increase in polyamine synthesis and endoplasmic reticulum stress (ERS) in cardiomyocytes. The present study was undertaken to elucidate the molecular interactions between polyamines, ERS and cardiac hypertrophy. Methods: Myocardial hypertrophy was simulated by incubating cultured neonatal rat cardiomyocytes in 100 nM isoproterenol (ISO). Polyamine deletion was achieved using 0.5 mM difluoromethylornithine (DFMO). Hypertrophy was estimated using cell surface area measurements, total protein concentrations and atrial natriuretic peptide (ANP) gene expression. Apoptosis was measured using flow cytometry and transmission electron microscopy. Expression of ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT) were analyzed via real-time PCR and Western blotting. Protein expression of ERS and apoptosis factors were analyzed using Western blotting. Results: DFMO (0.5 mM and 2 mM) treatments significantly attenuated hypertrophy and apoptosis induced by ISO in cardiomyocytes. DFMO also decreased lactate dehydrogenase (LDH) and malondialdehyde (MDA) level in the culture medium. In addition, DFMO (0.5 mM) down regulated the expression of ODC, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and Bax and up regulated the expression of SSAT and Bcl-2. Finally, these changes were partly reversed by the addition of exogenous putrescine (0.5 mM). Conclusion: The data presented here suggest that polyamine depletion could inhibit cardiac hypertrophy and apoptosis, which is closely related to the ERS pathway.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

Yan

Zhang

Wang

et al. 2014

Cell Physiol Biochem

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“…The protective effect of DFX was clearly reflected in returning the cardiac enzymes and isoenzymes after combination treatment to their normal levels. Several reports found similar increases in the serum cardiac enzyme GOT, LDH, and CK levels following the induction of myocardial necrosis in rats [29, 30]. …”

Section: Discussionmentioning

confidence: 52%

Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model

Al‐Shabanah

Aleisa

Hafez

et al. 2012

Oxidative Medicine and Cellular Longevity

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Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.

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“…Central to these protein alterations are fluctuations in polyamines (putrescine, spermidine and spermine), which are widely distributed in all cells and necessary for cell growth. Ornithine decarboxylase (ODC), the first and potentially rate-limiting enzyme of the polyamine pathway, is rapidly upregulated in response to various agents that induce a pathological cardiac hypertrophy, including thyroxine (Pegg et al, 1981), the β-adrenergic agonists isoproterenol (ISO) and clenbuterol, and the α1-adrenergic agonists phenylephrine and methoxamine (Cubria et al, 1998; Tipnis et al, 2000; Thompson et al,1992). Administration of α-difluoromethylornithine (DFMO), a suicide inactivator of ODC (Wallace and Fraser 2004), reduced polyamine content and attenuated ISO- and clenbuterol-induced cardiac hypertrophy (Cubria et al, 1998; Tipnis et al, 2000), suggesting that high ODC activity is a factor in the development of hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Attenuation of Isoproterenol-mediated Myocardial Injury in Rat by an Inhibitor of Polyamine Synthesis

Cited by 25 publications

References 46 publications

Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model

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

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