The antioxidant effects of a novel iron chelator salicylaldehyde isonicotinoyl hydrazone in the prevention of H2O2 injury in adult cardiomyocytes

Horackova, Magda; Ponka, Prem; Byczko, Zenobia

doi:10.1016/s0008-6363(00)00088-2

Cited by 74 publications

(55 citation statements)

References 25 publications

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“…8,11,12 In our study, iron-overloaded mice had increased mortality and displayed bradycardia. The effects of iron overload on mortality are consistent with observations showing that free radical-mediated lipid peroxidation alters cardiomyocyte electrophysiology 42,50 and Ca 2ϩ handling 20,43 and blockade of electrical conduction and sudden death in iron-overloaded guinea pigs. 51 Our strategy was to increase myocardial taurine levels to protect the cardiovascular system and prevent iron overloadinduced cardiovascular dysfunction, even though myocardial taurine levels were not affected by iron overload.…”

Section: Discussionsupporting

confidence: 87%

“…These aldehyde products are generated by free radical-induced lipid peroxidation and participate in cytotoxic reactions, leading to cellular dysfunction 48,49 including altered excitationcontraction coupling and electrophysiology and defective contractile function. 20,42,43,50 Indeed, a distinct feature of iron-overload cardiomyopathy in humans is the increased susceptibility to various arrhythmias, including bradyarrhythmias and cardiac death. 8,11,12 In our study, iron-overloaded mice had increased mortality and displayed bradycardia.…”

Section: Discussionmentioning

confidence: 99%

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Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model

et al. 2004

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Background-Iron overload has an increasing worldwide prevalence and is associated with significant cardiovascular morbidity and mortality. Elevated iron levels in the myocardium lead to impaired systolic and diastolic function and elevated oxidative stress. Taurine accounts for 25% to 50% of the amino acid pool in myocardium, possesses antioxidant properties, and can inhibit L-type Ca 2ϩ channels. Thus, we hypothesized that this agent would reduce the cardiovascular effects of iron overload. Methods and Results-Iron-overloaded mice were generated by intraperitoneal injection of iron either chronically (5 days per week for 13 weeks) or subacutely (5 days per week for 4 weeks). Iron overload causes increased mortality, elevated oxidative stress, systolic and diastolic dysfunction, hypotension, and bradycardia. Taurine supplementation increased myocardial taurine levels by 45% and led to reductions in mortality and improved cardiac function, heart rate, and blood pressure in iron-overloaded mice. Histological examination of the myocardium revealed reduced apoptosis and interstitial fibrosis in iron-overloaded mice supplemented with taurine. Taurine mediated reduced oxidative stress in iron-overloaded mice along with attenuation of myocardial lipid peroxidation and protection of reduced glutathione level. Conclusions-These results demonstrate that treatment with taurine reduces iron-mediated myocardial oxidative stress, preserves cardiovascular function, and improves survival in iron-overloaded mice. The role of taurine in protecting reduced glutathione levels provides an important mechanism by which oxidative stress-induced myocardial damage can be curtailed. Taurine, as a dietary supplement, represents a potential new therapeutic agent to reduce the cardiovascular burden from iron-overload conditions.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model

et al. 2004

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“…A concentration of 0.25 mmol/l consistently produced recordable negative inotropic effects, and 0.4 mmol/l produced marked, statistically significant, negative inotropism. These concentrations are also consistent with recent studies done by others (3,6,8,14) in the rodent myocardium. After several minutes, concentrations Ͼ0.4 mmol/l regularly produced contracture, cardiac arrest, and ventricular fibrillation.…”

Section: Hydrogen Peroxide and Acetaminophensupporting

confidence: 93%

“…Another purpose was to investigate several antioxidant mechanisms that might help explain the cardioprotective properties of acetaminophen, e.g., does acetaminophen attenuate the negative inotropic actions of exogenously administered hydrogen peroxide? The latter objective seemed important because it is well known that hydrogen peroxide releases hydroxyl radical via the Fenton reaction (2,14), and it has already been shown that acetaminophen attenuates the production of hydroxyl radical in the postischemic-reperfused myocardium (21).…”

mentioning

confidence: 99%

Acetaminophen and low-flow myocardial ischemia: efficacy and antioxidant mechanisms

Merrill

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Merrill, Gary F. Acetaminophen and low-flow myocardial ischemia: efficacy and antioxidant mechanisms. Am J Physiol Heart Circ Physiol 282: H1341-H1349, 2002; 10.1152/ajpheart.00716.2001.-In the current study, the cardioprotective efficacy of 0.35 mmol/l acetaminophen administered 10 min after the onset of a 20-min period of global, low-flow myocardial ischemia was investigated. Matched control hearts were administered an equal volume of KrebsHenseleit physiological buffer solution (vehicle). In separate groups of hearts, the concentration-dependent, negative inotropic properties of hydrogen peroxide and the ability of acetaminophen to attenuate these actions, as well as the effects of acetaminophen on ischemia-reperfusion-mediated protein oxidation, were studied. Acetaminophen-treated hearts regained a significantly greater fraction of baseline, preischemia control function during reperfusion than vehicle-treated hearts. For example, contractility [rate of maximal developed pressure in the left ventricle (ϮdP/dtmax)] after 10 min of reperfusion was 109 Ϯ 24 and 42 Ϯ 9 mmHg/s (P Ͻ 0.05), respectively, in the two groups. The corresponding pressure-rate products were 1,840 Ϯ 434 vs. 588 Ϯ 169 mmHg ⅐ beats ⅐ min Ϫ1 (P Ͻ 0.05). Acetaminophen attenuated peroxynitrite-mediated chemiluminescence in the early minutes of reperfusion (e.g., at 6 min, corresponding values for peak light production were ϳ8 ϫ 10 6 counts/min for vehicle vs. Ͻ4 ϫ 10 6 counts/min for acetaminophen, P Ͻ 0.05) and the negative inotropic effects of exogenously administered hydrogen peroxide (e.g., at 0.4 mmol/l hydrogen peroxide, pressure-rate products were ϳ1.0 ϫ 10 4 and 3.8 ϫ 10 3 mmHg ⅐ beats ⅐ min Ϫ1 in acetaminophen-and vehicle-treated hearts, respectively, P Ͻ 0.05). Ischemia-mediated protein oxidation was reduced by acetaminophen. The ability of acetaminophen to attenuate the damaging effects of peroxynitrite and hydrogen peroxide and to limit protein oxidation suggest antioxidant mechanisms are responsible for its cardioprotective properties during postischemia-reperfusion. coronary circulation; ventricular function; peroxynitrite; hydrogen peroxide ACETAMINOPHEN WAS INTRODUCED into Western medicine more than 100 years ago, and its pain-relieving and temperature-lowering actions have been under investigation for several decades (1, 9, 26). Potential cardiovascular properties of acetaminophen have gone undiscovered, in part, because no one has made an effort to do the experiments. This might have been influenced by standard textbooks of pharmacology that report that acetaminophen lacks efficacy in the cardiovascular system of mammals (12). The recent literature, however, suggests that investigators are beginning to fill this void. For example, Nakamoto et al. (22) reported beneficial effects of acetaminophen against gastric mucosal injury caused by ischemia-reperfusion in the rat. Farquhar et al. (10) reported reduced renal dysfunction in the stressed human kidney in the presence of acetaminophen vs. ibuprofen, and Colletti et al. (7) fou...

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“…Alternatively, iron chelation was achieved using salicylaldehyde isonicotinoyl hydrazone (SIH; 100 M) (27) (a kind gift from Dr. P. Ponka (McGill University, Montreal, Quebec, Canada)). SIH was prepared and kept at 4°C until used, as described elsewhere (27). Hemin (Frontier Scientific, Logan, UT) was dissolved in 0.2 N NaOH, neutralized to pH of 7.4 using 1 N HCl, and stored at Ϫ20°C until used.…”

Section: Reagentsmentioning

confidence: 99%

Heme Oxygenase-1 Modulates the Expression of Adhesion Molecules Associated with Endothelial Cell Activation

Soares

Seldon

Grégoire

et al. 2004

The Journal of Immunology

419

281

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Heme oxygenase-1 (HO-1) cleaves the porphyrin ring of heme into carbon monoxide, Fe2+, and biliverdin, which is then converted into bilirubin. Heme-derived Fe2+ induces the expression of the iron-sequestering protein ferritin and activates the ATPase Fe2+-secreting pump, which decrease intracellular free Fe2+ content. Based on the antioxidant effect of bilirubin and that of decreased free cellular Fe2+, we questioned whether HO-1 would modulate the expression of proinflammatory genes associated with endothelial cell (EC) activation. We tested this hypothesis specifically for the genes E-selectin (CD62), ICAM-1 (CD54), and VCAM-1 (CD106). We found that HO-1 overexpression in EC inhibited TNF-α-mediated E-selectin and VCAM-1, but not ICAM-1 expression, as tested at the RNA and protein level. Heme-driven HO-1 expression had similar effects to those of overexpressed HO-1. In addition, HO-1 inhibited the activation of NF-κB, a transcription factor required for TNF-α-mediated up-regulation of these genes in EC. Bilirubin and/or Fe2+ chelation mimicked the effects of HO-1, whereas biliverdin or carbon monoxide did not. In conclusion, HO-1 inhibits the expression of proinflammatory genes associated with EC activation via a mechanism that is associated with the inhibition of NF-κB activation. This effect of HO-1 is mediated by bilirubin and/or by a decrease of free intracellular Fe2+ but probably not by biliverdin or carbon monoxide.

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The antioxidant effects of a novel iron chelator salicylaldehyde isonicotinoyl hydrazone in the prevention of H2O2 injury in adult cardiomyocytes

Cited by 74 publications

References 25 publications

Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model

Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model

Acetaminophen and low-flow myocardial ischemia: efficacy and antioxidant mechanisms

Heme Oxygenase-1 Modulates the Expression of Adhesion Molecules Associated with Endothelial Cell Activation

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