Cardioprotective Effects of Mitochondrial-Targeted Antioxidants in Myocardial Ischemia/Reperfusion (I/R) Injury

Ondrasik, Regina; Chen, Qian; Navitsky, Katelyn; Chau, William; Lau, On Say; Devine, Issachar; Galbreath, Tyler; Barsotti, Robert; Young, Lindon H.

doi:10.17952/23aps.2013.064

Cited by 2 publications

(2 citation statements)

References 92 publications

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“…Our results for the 5 μM dose of Nox2ds-tat did not show significant recovery of post-reperfused cardiac function, but one may speculate that a low dose of Nox2ds-tat in conjunction with another selective peptide inhibitor of one of the other sources of I/R induced ROS may render significant results. For example, SS-31, a targeted mitochondrial antioxidant peptide, has been shown to dosedependently improve post-reperfused LVDP and reduce infarct size in rat hearts subjected to I (30 min)/R (45 min), in a manner similar to Nox2dstat [38,39]. While a low dose of these peptides administered alone did not yield significant results, a combination of Nox2ds-tat (5 μM) with SS-31 (10 μM) synergistically improved postreperfused LVDP by 63 ± 11% of initial values when compared to Nox2ds-tat (5 μM) alone (Table 1), SS-31 alone (10 μM), or control untreated I/R hearts that recovered to 47 ± 7% , 25 ± 1%, and 46 ± 6% (Table 1), respectively [38].…”

Section: Future Studiesmentioning

confidence: 99%

Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Chen¹,

Devine²,

Walker³

et al. 2016

Am. J. Biomed. Sci.

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Myocardial infarction is a form of ischemia/reperfusion (I/R) injury that causes cardiac contractile dysfunction and cell death. I/R injury is mediated, in part, by decreased endothelial-derived nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS) resulting in cell death. Cytokines released from I/R tissue activate G-protein coupled receptors that in turn stimulate NADPH oxidase to produce ROS. Thus, administration of a NADPH oxidase peptide inhibitor, Nox2ds-tat (formerly known as gp91ds-tat), may be a rational approach to attenuate I/R injury. Nox2ds-tat dose-dependently inhibited (10 μM -80 μM; n=5) phorbol 12-myristate13-acetate (n=21) induced polymorphonuclear leukocyte superoxide production up to 37 ± 7% (p<0.05; Fig. 3). Similarly, Nox2ds-tat dose-dependently attenuated I/R induced cardiac contractile dysfunction as evidenced by improved post-reperfused left ventricular developed pressure (LVDP) which recovered up to 77 ± 7% (5 μM-80 μM; p<0.05; n=6-7) of initial values (pre-ischemic values) at 45 min post-reperfusion when compared to control I/R hearts (n=14) that only recovered to 46 ± 6% from initial values for LVDP in isolated perfused rat hearts subjected to global I(30 min)/R(45 min) (Table 1). I/R control hearts exhibited an infarct size of 46 ± 2.1%, whereas I/R + Nox2ds-tat hearts exhibited infarct sizes of 30 ± 4% (5 μM), 15 ± 1.4% (10 μM), 23 ± 2.0% (40 µM), and 19 ± 1.6% ( 80µM) (p<0.01 vs. control I/R hearts; Figure 4, Panel A-B). Regarding in vivo assessments, Nox2ds-tat (4.1 mg/kg, IV) significantly reduced blood H 2 O 2 (1.4 µM) and increased endothelial-derived blood NO (127 nM) at 45 min reperfusion

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Section: Future Studiesmentioning

confidence: 99%

Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Chen¹,

Devine²,

Walker³

et al. 2016

Am. J. Biomed. Sci.

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“…At the end of the experiment, the heart was crosssectioned into 2 mm sections from apex to base. The heart crosssections were subjected to 1% Triphenyltetrazolium Chloride (TTC) staining for 15 min at 37 °C to determine infarct size as previously described [20,27,28].…”

Section: Myocardial I/r Proceduresmentioning

confidence: 99%

Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

2019

J Cardiobiol

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Background and purpose:The principal cause of cardiomyocyte dysfunction and necrosis resulting from Ischemia/Reperfusion (I/R) injury is the production and release of Reactive Oxygen Species (ROS) from damaged mitochondria. Mitochondrial ROS-mediated oxidation of cellular proteins and lipids disrupts both cellular metabolism and organelle integrity, leading to depletion of ATP stores and an increase in intracellular calcium (Ca 2+ ) levels. Thus, attenuation of I/R-induced ROS production has been a therapeutic strategy to salvage damaged cardiomyocytes and thereby limit cardiac functional impairment and infarct size [1]. Previous studies have tested the effectiveness of mitochondrial-targeted antioxidants. Mitoquinone (MitoQ) was effective in reducing I/R injury when given only prior to prolonged ischemia, while Szeto-Schiller (SS)-31 was effective when given either prior to ischemia or at the beginning of reperfusion. This study was undertaken to determine whether these agents are effective in limiting myocardial and hindlimb I/R injury when given during the first 5min of reperfusion only, and thereby support the premise that mitochondrial damage underlies reperfusion-induced cell death during the initial minutes of reperfusion.Experimental approach: Male Sprague-Dawley rats (275-325 g) were randomized into myocardial or hindlimb I/R groups. Isolated, retrogradely perfused hearts were subjected to global I(30 min)/R(45 min). Hearts were treated with MitoQ (1-20 µM), SS-31 (10-100 µM), or plasma (control) added to the perfusate at the onset of reperfusion and was assessed for cardiac function and infarct size. In the hindlimb experiments, either hydrogen peroxide (H 2 O 2 ) or Nitric Oxide (NO) sensors were placed randomly in both the right and left femoral veins of the same animal. One limb was subjected to I(30 min)/R(45 min) by reversibly clamping the femoral artery/vein, while the other limb served as a sham. The animal received an intravenous (i.v.) bolus of either MitoQ (1.8 mg kg -1 ), SS-31 (2.5 mg kg -1 ), or saline (control) at the beginning of reperfusion. The difference in blood H 2 O 2 or NO between the femoral vein of ischemic and sham limbs in each animal was continuously measured to assess the effects of the drugs. Key results:In the myocardial I/R model, MitoQ and SS-31 given upon reperfusion significantly improved cardiac function and reduced infarct size compared to untreated control hearts. In the hindlimb I/R model, elevations in blood H 2 O 2 levels and reductions in blood NO, both indices of elevated ROS, were significantly attenuated by both MitoQ and SS-31 given upon reperfusion compared to saline treated control animals. Conclusion and implications:The results indicate that mitochondrial-derived ROS is a major contributor to reperfusion injury and that MitoQ and SS-31 work expeditiously to attenuate ROS in that both agents improve cardiac function and limit infarct size when administered only at the onset of reperfusion. The data suggest that MitoQ or SS-31 would be an effective adjuvant...

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Cardioprotective Effects of Mitochondrial-Targeted Antioxidants in Myocardial Ischemia/Reperfusion (I/R) Injury

Cited by 2 publications

References 92 publications

Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

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