Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion

Arakawa, Masayuki; Yasutake, Masahiro; Miyamoto, Masaaki; Takano, Teruo; Asoh, Sadamitsu; Ohta, Shigeo

doi:10.1016/j.lfs.2007.03.012

Cited by 26 publications

(10 citation statements)

References 37 publications

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“…Several lines of evidence support the concept that activation of caspase-3 contributes to ischemic neuronal death. The caspase-3-like activity increases progressively between 1 and 24 h of reperfusion [25]. Furthermore, treatment with caspase-3 inhibitors reduced heart and brain injury, even though caspase-3 inhibitors were applied several hours after the insult [26,27].…”

Section: Effect Of a Brasiliensis Polysaccharide On Caspase-3 Level mentioning

confidence: 99%

Characterization of chemical composition of Agaricus brasiliensis polysaccharides and its effect on myocardial SOD activity, MDA and caspase-3 level in ischemia–reperfusion rats

Zhang

et al. 2010

International Journal of Biological Macromolecules

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Section: Effect Of a Brasiliensis Polysaccharide On Caspase-3 Level mentioning

confidence: 99%

Characterization of chemical composition of Agaricus brasiliensis polysaccharides and its effect on myocardial SOD activity, MDA and caspase-3 level in ischemia–reperfusion rats

Zhang

et al. 2010

International Journal of Biological Macromolecules

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“…Arakawa M et al found no difference in infarct size in isolated perfused rat hearts treated with three concentrations (i.e. 5, 50, and 500 nM) of an anti-apoptotic drug (FNK) constructed from Bcl-x(L), a member of the Bcl-2 apoptotic regulator protein family [41]. In their study, all three concentrations tested resulted in a reduction in infarct size to ~30±5% (n=8) compared to 47±5% (n=8) in control hearts.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

2017

J Cardiobiol

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Background: The generation of reactive oxygen species (ROS) during myocardial ischemia (I)/reperfusion (R) contributes to postreperfusion cardiac injury. The increase in ROS is attributed in part to the uncoupling of endothelial nitric oxide synthase (eNOS) that produces ROS instead of nitric oxide (NO) and mitochondrial derived ROS which in part is derived from opening of mitochondrial ATPsensitive K + channels (mK ATP ). Both the activity of uncoupled eNOS and the opening of mK ATP channels in mitochondria are stimulated by protein kinase C epsilon (PKCε) that is activated during reperfusion. We hypothesize that a cell permeable PKCε peptide inhibitor, (N-myristic acid-EAVSLKPT, Myr-PKCε-) given at reperfusion will improve postreperfused cardiac function and attenuate infarct size compared to untreated isolated perfused rat hearts subjected to ischemic reperfusion injury. Methods:Male Sprague-Dawley rats (275-325 g) were anesthetized with sodium pentobarbital (60 mg/kg) and anticoagulated with heparin 1000 units given intraperitoneally. The hearts were excised and attached to a Langendorff perfusion system. All hearts were subjected to 30 min of global ischemia, followed by 90 min of reperfusion. Myr-PKCε-was dissolved in Krebs' buffer and infused during the first 10 min of reperfusion at final concentrations of 5, 10 and 20 µM.Results: Myr-PKCε-treated hearts (10 and 20 μM) exhibited significant improvement in post-reperfused cardiac function at 90 min compared to untreated controls. The maximal rate of left ventricular developed pressure generation (+dP/dt max ) of Myr-PKCε-treated hearts showed significant recovery to 56±4% (10 μM, p<0.05, n=8) and 50±3%; (20 μM, p<0.05, n=8) of initial baseline values. By contrast, the +dP/ dt max of both untreated control hearts (n=9) and those treated with the lowest concentration of Myr-PKCε-(5 μM, n=8) recovered to only 30±4% and 33±4% of initial baseline values, respectively. Interestingly, all Myr-PKCε-treated hearts (5-20 μM) showed significant reduction in infarct size to 28±2% compared to untreated control hearts, which averaged 38±3% (p<0.05, n=9). Conclusion:The results suggest that Myr-PKCε-given at reperfusion effectively reduces infarct size, improves cardiac function and is a putative treatment that could aid in clinical myocardial infarction/ organ transplantation patient recovery. [3][4][5][6][7]. The necessity for effective pharmacological intervention still exists, despite numerous basic studies firmly establishing that I/R injury can be delayed or even reduced by the introduction of cardioprotective agents or strategies prior to a prolonged ischemic insult (preconditioning) or at the start of reperfusion [1,8]. Such interventions have been shown to reduce infarct size, attenuate the frequency and severity of reperfusion-induced arrhythmias, and prevent endothelial dysfunction [9][10][11][12][13].Preconditioning of the myocardium can be induced by several rounds of brief ischemia (i.e. less than 4 min) followed by several rounds of brief reperfus...

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“…Ohta's group (143) ligated the TAT domain to the super-antiapoptotic factor FNK to produce the PTD-FNK fusion protein. PTD-FNK fusion protein was transduced efficiently into cells, localized into mitochondria, and protected both neuronal and cardiac cells from apoptosis induced by ischemia in culture as well as in animal models (71,143,160). Similarly, TAT-Bcl-2 fusion protein protected neurons from apoptotic cell death in culture (161).…”

Section: Organelle Targetingmentioning

confidence: 97%

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

Papadopoulou

Tsiftsoglou

2011

Pharm Res

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Protein therapy is considered an alternative approach to gene therapy for treatment of genetic-metabolic disorders. Human protein therapeutics (PTs), developed via recombinant DNA technology and used for the treatment of these illnesses, act upon membrane-bound receptors to achieve their pharmacological response. On the contrary, proteins that normally act inside the cells cannot be developed as PTs in the conventional way, since they are not able to "cross" the plasma membrane. Furthermore, in mitochondrial disorders, attributed either to depleted or malfunctioned mitochondrial proteins, PTs should also have to reach the subcellular mitochondria to exert their therapeutic potential. Nowadays, there is no effective therapy for mitochondrial disorders. The development of PTs, however, via the Protein Transduction Domain (PTD) technology offered new opportunities for the deliberate delivery of human recombinant proteins inside eukaryotic subcellular organelles. To this end, mitochondrial disorders could be clinically encountered with the delivery of human mitochondrial proteins (engineered via recombinant DNA and PTD technologies) at specific intramitochondrial sites to exert their function. Overall, PTD-mediated Protein Replacement Therapy emerges as a suitable model system for the therapeutic approach for mitochondrial disorders.

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Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion

Cited by 26 publications

References 37 publications

Characterization of chemical composition of Agaricus brasiliensis polysaccharides and its effect on myocardial SOD activity, MDA and caspase-3 level in ischemia–reperfusion rats

Characterization of chemical composition of Agaricus brasiliensis polysaccharides and its effect on myocardial SOD activity, MDA and caspase-3 level in ischemia–reperfusion rats

Protein Kinase C Epsilon PeptideInhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

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