A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats

Song, Woo-Hyuk; Shin, Jinho; Lee, Jaeung; Kim, Hyun‐Joong; Oh, Dong Ju; Edelberg, Jay M.; Wong, S. Chiu; Szeto, Hazel H.; Hong, Mun K.

doi:10.1097/00019501-200509000-00011

Cited by 30 publications

(17 citation statements)

References 10 publications

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“…In contrast, in another study, SS-20, which has no scavenging ability, impeded myocardial stunning when administered upon reperfusion. This ability of SS-02 to prevent myocardial stunning has been confirmed in an in vivo rat model [66].These findings with SS peptides support the hypothesis that ROS play a major role in reperfusion-induced myocardial stunning.…”

Section: Mitochondria-targeted Peptide Antioxidantssupporting

confidence: 60%

Mitochondria-Targeted Antioxidant Peptides

Rocha

Hernández‐Mijares²,

Garcia-Malpartida³

et al. 2010

CPD

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Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is part of the disease process. These ROS are released from different sources, and in particular from mitochondria. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are unclear, oxidative stress seems to play an important role. ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects that excessive ROS production can produce. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. The antioxidants available until now have not proved to be particularly effective against many of these disorders. It is possible that these antioxidants do not reach the sites of free radical generation, especially when mitochondria are the primary source of ROS. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The SS (Szeto-Schiller) peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. These SS peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. By reducing mitochondrial ROS, they inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Preclinical studies support the use of these peptides for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, the few that have been studied are promising agents for the treatment of diseases.

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Section: Mitochondria-targeted Peptide Antioxidantssupporting

confidence: 60%

Mitochondria-Targeted Antioxidant Peptides

Rocha

Hernández‐Mijares²,

Garcia-Malpartida³

et al. 2010

CPD

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“…The multiple injection paradigm was used, because there is a biphasic ROS production and sustained CD36 expression in post-ischemic brain (1,26). The dosage of SS31 used in the present study was based on the dosage previously used in protection against myocardial ischemia (22) and in a model of neurodegeneration (27).…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…Unlike other antioxidants, the SS peptides target mitochondria and protect mitochondria against mitochondrial permeability transition, swelling, and cytochrome c release (2) and prevent t-butylhydroperoxide-induced apoptosis (20). These peptide antioxidants are very effective in preventing myocardial stunning and reducing infarct size following cardiac ischemia reperfusion (2,(21)(22)(23). To exploit an antioxidant approach by targeting CD36, the present study investigated whether the SS31 antioxidant peptide attenuates cerebral ischemia-induced injury and whether the peptide-induced neuroprotection involves the down-regulation of CD36 expression and function.…”

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confidence: 99%

A Novel Cell-permeable Antioxidant Peptide, SS31, Attenuates Ischemic Brain Injury by Down-regulating CD36

Cho

Szeto

Kim

et al. 2007

Journal of Biological Chemistry

159

126

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Oxidative stress is implicated in the pathogenesis of ischemia/ reperfusion injury. Recently, we demonstrated that activation of CD36, a class B scavenger receptor, mediates free radical production and tissue injury in cerebral ischemia (1). Oxidized low density lipoproteins (oxLDL) are among the ligands that bind to CD36 and are elevated in acute cerebral infarction. SS31 is a cell-permeable antioxidant peptide that reduces intracellular free radicals and inhibits LDL oxidation/lipid peroxidation (2). The current study was designed to investigate whether treatment with SS31 normalizes ischemia-induced redox changes and attenuates CD36-mediated tissue injury. C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO). Redox status and infarct volume were measured in animals treated with either saline or SS31. Oxidative stress induced by ischemia/reperfusion profoundly depleted glutathione (GSH) concentrations in the ipsilateral cortex and striatum. Treating mice with SS31 immediately after reperfusion significantly attenuated ischemia-induced GSH depletion in the cortex and reduced infarct size. By contrast, the protective effect of SS31 was absent in CD36 knock-out mice, indicating that SS31 is acting through inhibition of CD36. Treating C57BL/6 mice with SS31 reduced CD36 expression in postischemic brain and mouse peritoneal macrophages (MPM). Further in vitro studies revealed that SS31 attenuated oxLDL-induced CD36 expression and foam cell formation in MPM. These in vivo and in vitro studies indicate that the down-regulation of CD36 by novel class antioxidant peptides may be a useful strategy to treat ischemic stroke victims. Generation of reactive oxygen species (ROS)2 and depletion of intracellular antioxidants following cerebral ischemia/reperfusion are hallmarks of oxidative stress and lead to tissue injury. Glutathione and ascorbate are major endogenous cerebral antioxidants that serve as biochemical markers of intracellular redox status (3). It is generally accepted that these antioxidants are important for protection of brain during post-ischemic oxidative stress, although dynamic interactions among antioxidants in vivo are not entirely clear. Depletion of intracellular antioxidants has been associated with stroke pathology and repletion of antioxidant status has reduced neuronal damage but has produced inconsistent improvement in stroke outcome (4 -8). Ischemic injury also causes a local inflammatory reaction by activated microglia and infiltrated inflammatory cells that further release pro-inflammatory cytokines and ROS within the injured site.CD36, a glycosylated surface receptor, belongs to a class B scavenger receptor and is localized in lipid rafts of plasma membrane and in mitochondria (9 -11). It is expressed on microglia, macrophages, microvascular endothelium, cardiac and skeletal muscle, adipocytes, and platelets and recognizes a variety of ligands including oxidized low density lipoproteins (oxLDL), advanced glycation end products, long chain fatty acids, fibrillar ␤-a...

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“…Previously we showed that a potent opioid peptide, 2 0 ,6 0 -dimethyl-tyrosine (Dmt)-D-Arg-Phe-Lys-NH 2 (Dmt-DALDA or SS-02) , could prevent myocardial stunning in the isolated guinea pig heart [1] and in a rat ischemiareperfusion model [2]. Opioids, including morphine, have been shown to provide cardioprotection during ischemia [3].…”

Section: Introductionmentioning

confidence: 99%

Potent mitochondria-targeted peptides reduce myocardial infarction in rats

Cho¹,

Won²,

et al. 2007

Coronary Artery Disease

Self Cite

130

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This study shows that pretreatment with both SS-31 and SS-20 significantly reduced myocardial lipid peroxidation and infarct size in ischemia-reperfusion injury, and suggests that the cardioprotective properties of 2',6'-dimethyl-tyrosine-D-Arg-Phe-Lys-NH2 was primarily mediated by its antioxidant properties. As SS-20 does not scavenge reactive oxygen species, it most likely reduces reactive oxygen species production during ischemia-reperfusion.

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A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats

Abstract: 2',6'-Dimethyltyrosine-D-Arg-Phe-Lys-NH2 provides a cardioprotective effect against myocardial ischemia and reperfusion in vivo.

Cited by 30 publications

References 10 publications

Mitochondria-Targeted Antioxidant Peptides

Mitochondria-Targeted Antioxidant Peptides

A Novel Cell-permeable Antioxidant Peptide, SS31, Attenuates Ischemic Brain Injury by Down-regulating CD36

Potent mitochondria-targeted peptides reduce myocardial infarction in rats

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