A highly potent peptide analgesic that protects against  ischemia-reperfusion-induced myocardial stunning

Wu, Dunli; Soong, Yi; Zhao, Guangjie; Szeto, Hazel H.

doi:10.1152/ajpheart.00193.2002

Cited by 39 publications

(26 citation statements)

References 32 publications

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“…In contrast, SS-20, which has no antioxidant activity, was unable to protect the ischemic heart against reperfusion stunning. We had previously reported that SS-02 can prevent myocardial stunning even when administered only during reperfusion (42), consistent with antioxidation as the mechanism of action. The ability of SS-02 to prevent stunning has been confirmed in rats in vivo.…”

Section: Discussionsupporting

confidence: 75%

“…Ischemia-Reperfusion Studies-Details of the isolated perfused guinea pig heart model have been published previously (42). Isolated hearts were perfused continuously with either Krebs-Henseleit solution or Krebs-Henseleit solution containing various SS peptides and allowed to stabilize for 30 min.…”

Section: Measurement Of Antioxidant Properties Of Ss Peptides In Vitro-mentioning

confidence: 99%

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Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury

Zhao

Zhao²,

Wu³

et al. 2004

Journal of Biological Chemistry

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723

693

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Reactive oxygen species (ROS) play a key role in promoting mitochondrial cytochrome c release and induction of apoptosis. ROS induce dissociation of cytochrome c from cardiolipin on the inner mitochondrial membrane (IMM), and cytochrome c may then be released via mitochondrial permeability transition (MPT)-dependent or MPT-independent mechanisms. We have developed peptide antioxidants that target the IMM, and we used them to investigate the role of ROS and MPT in cell death caused by t-butylhydroperoxide (tBHP) and 3-nitropropionic acid (3NP). The structural motif of these peptides centers on alternating aromatic and basic amino acid residues, with dimethyltyrosine providing scavenging properties. These peptide antioxidants are cell-permeable and concentrate 1000-fold in the IMM. They potently reduced intracellular ROS and cell death caused by tBHP in neuronal N 2 A cells (EC 50 in nM range). They also decreased mitochondrial ROS production, inhibited MPT and swelling, and prevented cytochrome c release induced by Ca 2؉ in isolated mitochondria. In addition, they inhibited 3NP-induced MPT in isolated mitochondria and prevented mitochondrial depolarization in cells treated with 3NP. ROS and MPT have been implicated in myocardial stunning associated with reperfusion in ischemic hearts, and these peptide antioxidants potently improved contractile force in an ex vivo heart model. It is noteworthy that peptide analogs without dimethyltyrosine did not inhibit mitochondrial ROS generation or swelling and failed to prevent myocardial stunning. These results clearly demonstrate that overproduction of ROS underlies the cellular toxicity of tBHP and 3NP, and ROS mediate cytochrome c release via MPT. These IMM-targeted antioxidants may be very beneficial in the treatment of aging and diseases associated with oxidative stress.

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Section: Discussionsupporting

confidence: 75%

Section: Measurement Of Antioxidant Properties Of Ss Peptides In Vitro-mentioning

confidence: 99%

Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury

Zhao

Zhao²,

Wu³

et al. 2004

Journal of Biological Chemistry

Self Cite

723

693

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“…These properties make the SS peptides highly effective in prevention and treatment of IR injury (311). The Tyr-containing SS peptides can significantly reduce reperfusion arrhythmias, myocardial contractile function, and infarct size after myocardial ischemia (54); attenuate infarct size after cerebral injury (254); reduce acute kidney injury after renal IR (346); protect skeletal muscles; and preserve normal cellular architecture after 3 h of hind limb ischemia (350). Most importantly, these SS peptides are effective even when administered on reperfusion and require no pretreatment.…”

Section: A Tppmentioning

confidence: 99%

Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

Dai

Chen²,

Johnson³

et al. 2012

Antioxidants & Redox Signaling

278

223

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Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/ insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several ''anti-aging'' strategies that treat CVDs and improve healthy cardiac aging.

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“…SS31 belongs to a family of cell-permeable mitochondria-targeted peptide antioxidants (ss peptides) that was first reported to inhibit ROS production, mitochondrial depolarization, and (I/R)-induced myocardial stunning in early 2000s [14,15]. SS31 is a tetrapeptide with a dimethyltyrosine residue, which provides ROS scavenging activity [15].…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Antioxidant Peptide SS31 Prevents Hypoxia/Reoxygenation-Induced Apoptosis by Down-Regulating p66Shc in Renal Tubular Epithelial Cells

Zhao

Han

Zhang

et al. 2013

Cell Physiol Biochem

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Background/Aims: Ischemia/reperfusion injury plays a crucial role in renal transplantation and represents a significant risk factor for acute kidney injury and delayed graft function. Mitochondria-targeted antioxidant peptide SS31 has been shown to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The present study was carried out to investigate whether the pretreatment of SS31 could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting p66Shc. Methods: The cultured rat renal proximal tubular cell line NRK52E cells were exposed to 24 h hypoxia (5% CO₂, 1% O₂, 94% N₂) followed by 6 h reoxygenation (5% CO₂, 21% O₂, 74% N₂). SS31 was added to the culture medium 4 h prior to the treatment. Then the cell viability, apoptosis, and oxidative stress levels were determined. In addition, western blot analysis was performed to determine the expression of p66Shc, p-p66Shc, cytochrome c, and caspase-3. Results: H/R induced apoptotic cell death, accompanied with activation of total and p-p66Shc in NRK52E cells. Pretreatment with SS31 or overexpression of a dominantnegative Ser36 mutant p66Shc (p66Shc S36A) or p66Shc siRNA prevented cell death, whereas the protection effect of SS31 was completely blocked by overexpression of wild-type p66Shc. Furthermore, SS31 pretreatment reduced H/R-induced intracellular oxidative stress, cytochrome c translocation to the cytoplasm, and caspase-3 activation through inhibiting p66Shc. Conclusion: This study revealed that SS31 pretreatment serves a protective role against H/R-induced apoptosis of human renal tubular epithelial cells, and the mechanism is related to suppression of p66Shc.

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A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning

Cited by 39 publications

References 32 publications

Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury

Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury

Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

Mitochondria-Targeted Antioxidant Peptide SS31 Prevents Hypoxia/Reoxygenation-Induced Apoptosis by Down-Regulating p66Shc in Renal Tubular Epithelial Cells

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