The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart

Omar, Bassam; McCord, Joe M.

doi:10.1016/0891-5849(90)90124-2

Cited by 121 publications

(49 citation statements)

References 21 publications

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“…The decreased levels of MnSOD biochemical activity following injection of 1000 mg of MnSOD plasmid DNA may have resulted from plasmid overload, interference, or decreased endogenous murine MnSOD expression as a reactive cellular process to high transgene levels. [16][17][18] Further studies will be required to test these hypotheses. The data suggest that the protective effects of MnSOD-PL injections may be optimal at lower plasmid doses.…”

Section: Discussionmentioning

confidence: 99%

Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase–plasmid/liposomes (MnSOD–PL) during lung radioprotective gene therapy

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase–plasmid/liposomes (MnSOD–PL) during lung radioprotective gene therapy

et al. 2003

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“…This result is in agreement with our current studies where inhalation of 250 mg or higher resulted in similar levels of MnSOD biochemical activity. McCord and coworkers [47][48][49] have reported that expression of high levels of MnSOD is not beneficial or protective. It is possible that a protective mechanism in the lung may regulate levels of MnSOD.…”

Section: Lung Irradiation Protection By Inhalation Of Mnsod-pl M Carpmentioning

confidence: 99%

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

et al. 2005

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Intratracheal injection of manganese superoxide dismutaseplasmid/liposome (MnSOD-PL) complexes has been demonstrated to delay the onset and reduce the extent of ionizing irradiation-induced murine pulmonary organizing alveolitis/ fibrosis. To facilitate translation of this modality to clinical fractionated radiotherapy, inhalation delivery of MnSOD-PL was developed using an ultrasonic nebulizer. Transgene product was quantitated by immunohistochemical quantitation and pulmonary tissue levels of MnSOD biochemical activity. C57BL/6NHsd female mice demonstrated a plasmid dose-dependent increased expression of MnSOD transgene product over the range of 250 mg-2.5 mg of MnSOD-PL administered over a constant 5 min interval. Delivery of a constant concentration of 500 mg of MnSOD-PL with varying times of administration ranging from 0.5 to 10 min demonstrated optimal MnSOD expression at 5 min. Mice pretreated by inhalation delivery of MnSOD-PL demonstrated significantly improved survival after 20 Gy single fraction irradiation to both lungs compared to LacZ-PL inhalation-treated or irradiated control mice. Mice receiving 10 fractions of 3.5 cGy demonstrated increased pulmonary MnSOD transgene product activity by a protocol of every Monday-Wednesday or daily inhalation of MnSOD-PL. Thus, inhalation radioprotective gene therapy using MnSOD-PL provides a practical and effective method for delivery of lung-specific radioprotection during fractionated radiotherapy protocols in a mouse model. Gene Therapy (2005) 12, 685-693.

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“…24 The same bell-shaped dose-response curve was observed with Mn-SOD, suggesting that the lack of protection at higher doses was not due to peroxidase activity. Although the mechanism of this adverse effect is unclear, the rate of generation of hydrogen peroxide from h-SOD may exceed the capability of endogenous catalase and/or glutathione peroxidase to detoxify hydrogen peroxide, or perhaps overscavenging of superoxide might eliminate an important termination step of lipid peroxidation, namely, reaction of the protonated form of superoxide with lipid peroxide radicals.…”

Section: Discussionmentioning

confidence: 50%

“…23,24 A recent study from McCord's laboratory (Omar and McCord25) demonstrated that 50 minutes of pretreatment with h-SOD (Cu-Zn) was required in an intact rabbit model of regional ischemia/reperfusion for significant concentrations of h-SOD to be measurable in cardiac lymph. It is unknown whether preexisting collateral channels could have allowed h-SOD access to the vascular distribution of the occluded coronary artery, even if h-SOD treatment had been initiated in the emergency room.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.

et al. 1994

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BACKGROUND Animal studies have demonstrated a burst of oxygen free radical generation after reperfusion of ischemic myocardium that could be blocked by administration of the free radical scavenger recombinant human superoxide dismutase (h-SOD). A multicenter, randomized, placebo-controlled clinical trial was designed to test the hypothesis that free radical-mediated reperfusion injury could be reduced by intravenous administration of h-SOD begun before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute transmural myocardial infarction. METHODS AND RESULTS One hundred twenty patients were randomized to receive placebo (n = 59) or h-SOD (n = 61) given as a 10-mg/kg intravenous bolus followed by a 60-minute infusion of 0.2 mg.kg-1.min-1. Left ventricular function was analyzed via paired contrast left ventriculograms performed before PTCA and after 6 to 10 days and paired radionuclide ventriculograms performed within 24 hours of PTCA and after 4 to 6 weeks. Both h-SOD- and placebo-treated patients showed improvement in global and regional left ventricular function after successful reperfusion. Compared with the placebo group, no additional improvement was observed in the patients treated with h-SOD. CONCLUSIONS The results of this clinical trial failed to demonstrate a beneficial effect of h-SOD on global or regional left ventricular function in patients who underwent successful PTCA for treatment of acute myocardial infarction.

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The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart

Cited by 121 publications

References 21 publications

Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase–plasmid/liposomes (MnSOD–PL) during lung radioprotective gene therapy

Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase–plasmid/liposomes (MnSOD–PL) during lung radioprotective gene therapy

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.

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