Dystrophin is a possible end-target of ischemic preconditioning against cardiomyocyte oncosis during the early phase of reperfusion

Kyoi, Shiori; Otani, Hajime; Hamano, Ayako; Matsuhisa, Seiji; Akita, Yuzo; Fujiwara, Hiroyoshi; Hattori, Reiji; Imamura, Hiroji; Kamihata, Hiroshi; Iwasaka, Toshiji

doi:10.1016/j.cardiores.2006.01.004

Cited by 19 publications

(19 citation statements)

References 27 publications

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“…Interestingly, IPC-induced restoration of sarcolemmal dystrophin after reperfusion was dependent on mitochondrial ATP synthesis. 9 These results support the notion that both the sarcolemmal level of dystrophin and mechanical stress during reperfusion are factors determining sarcolemmal permeability and thus susceptibility to reperfusion injury.…”

Section: Article P 2393supporting

confidence: 82%

“…They found that ischemic preconditioning (IPC) restores sarcolemmal dystrophin and suppresses the increase in sarcolemmal permeability after reperfusion. 8, 9 These effects of IPC were enhanced by using BDM to temporarily arrest the heart beat during the early reperfusion period. Interestingly, IPC-induced restoration of sarcolemmal dystrophin after reperfusion was dependent on mitochondrial ATP synthesis.…”

Section: Article P 2393mentioning

confidence: 99%

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Cytoskeletal Proteins

Miura

2010

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp arcolemmal rupture, a hallmark of cardiomyocyte necrosis after ischemia -reperfusion, is induced by an increase in sarcolemmal fragility during ischemia, as well as by mechanical stress on the sarcolemma imposed by cell edema and the restoration of contraction upon reperfusion. 1 How ischemia induces fragility of the sarcolemma remains unclear, but a putative mechanisms is loss of cytoskeletal proteins. Long-sustained ischemia reduces sarcolemmal levels of dytrophin, β-dytroglycan, γ-sarcoglycan, vinculin, spectrin and vinculin, and dystrophin is the most sensitive of these structural proteins to ischemia. 2-4 Dystrophin connects F-actin in the subsarcolemmal cytoskeleton or the sarcomeres to δ-dystroglycan spanning the cell membrane, and is a member of the dystrophin glycoprotein complex (DGC). 5 Ischemia induces translocation of dystrophin from the sarcolemma to the intracellular pools, and this ischemiainduced loss of dystrophin in the sarcolemma has been shown to correlate with formation of sarcolemmal blebs. 2 On the other hand, in isolated cardiomyocytes the loss of spectrin from the sarcolemma has correlated with fragility of the cell to hypo-osmotic stress. 2 However, these findings do not necessarily indicate that loss of dystrophin and/or spectrin is sufficient for priming cardiomyocytes for sarcolemmal rupture upon reperfusion. Article p 2393Dystrophin and other members of the DGC are crucial for physiological regulation of membrane permeability. In myocardium in which dystrophin or sarcoglycans is genetically deleted, permeability of the sarcolemma assessed by influx of cell-impermeable tracers (eg, Evans Blue [EB] and albumin) is significantly increased. 5,6 Intracellular Ca 2+ levels are elevated in these cardiomyocytes possibly by upregulation of the Ca 2+ -permeable, growth-factor-regulated channel (TRPV2). 7 Ca 2+ influx via this channel potentially aggravates cell injury by activation of a Ca 2+ -activated protease, calpain, leading to a vicious cycle of loss of structural membrane protein, increased sarcolemmal instability and Ca 2+ overload. This vicious cycle has been proposed as a mechanism of progressive cell loss and heart failure in animals and patients with mutations in the DGC. 5, 6 Otani et al have conducted a series of studies to address the causative relationship between dystrophin loss from the sarcolemma during ischemia and reperfusion-induced cardiomyocyte necrosis. 4,8-10 They first showed in the rat myocardium that approximately 60% of membrane dystrophin was lost after 30 min of ischemia and that further loss of dystrophin occurred after reperfusion. 4 Inhibition of ventricular contraction by 2,3-butanedione monoxime (BDM) during reperfusion did not affect the loss of sarcolemmal dystrophin, but did inhibit the increase in sarcolemmal permeability to EB after reperfusion, indicating that mechanical stress is crucial for the pathological increase in sarcolemmal permeability upon re...

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Section: Article P 2393supporting

confidence: 82%

Section: Article P 2393mentioning

confidence: 99%

Cytoskeletal Proteins

Miura

2010

Circ J

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“…This concentration of BDM has been shown to abolish contractility without an apparent toxic effect in the same experimental model. 24 The PI3K inhibitor, LY294002 (Calbiochem, San Diego, CA, USA), was added at a concentration of 10 μmo/L into the buffers in the presence or absence of BDM for the first 400 s of reperfusion (equivalent to the duration of IPost).…”

Section: Animal Preparation and Perfusion Techniquementioning

confidence: 99%

“…24 The number of EB-positive and -negative cardiomyocytes was counted for 60 high-power fields (magnification × 600) from the endocardium through the epicardium of the mid-LV free wall, and the percentage of EB-positive cardiomyocytes was calculated.…”

Section: Detection Of Oncotic Cardiomyocytesmentioning

confidence: 99%

“…20, 21 We have previously reported that dystrophin is translocated from the sarcolemma during ischemia, 22, 23 and that redistribution of dystrophin to the sarcolemma during reperfusion depends on mitochondrial ATP generation. 24 Therefore, despite the fact that IPost protects the mitochondria, it is anticipated that the inhibition of aerobic ATP generation during IPost is detrimental for the recovery of sarcolemmal integrity and renders cardiomyocytes susceptible to oncosis. Therefore, developing strategies that can protect cardiomyocytes depleted of dystrophin from oncosis during IPost might be necessary to enhance the efficacy of IPost.…”

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Inhibition of Contractile Activity During Postconditioning Enhances Cardioprotection by Restoring Sarcolemmal Dystrophin Through Phosphatidylinositol 3-Kinase

Moriguchi

Otani

Yoshioka

et al. 2010

Circ J

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Background: Although ischemic postconditioning (IPost) confers cardioprotection by protecting the mitochondria though the activation of phosphatidylinositol 3-kinase (PI3K), a potential drawback of IPost is impairment of aerobic ATP generation during reperfusion by repeated ischemia. This decrease in ATP might inhibit the restoration of sarcolemmal dystrophin, which is translocated during ischemia, and render cardiomyocytes susceptible to contraction-induced oncosis. Methods and Results:Isolated rat hearts were subjected to 30 min ischemia and 120 min reperfusion. IPost induced by 20 cycles of 10-s reperfusion and 10-s ischemia enhanced the activation of PI3K as evidenced by the increased phosphorylation of Akt, but had no effect on myocardial ATP, restoration of sarcolemmal dystrophin, or cardiomyocyte oncosis during IPost. Administration of the contractile blocker, 2,3-butanedione monoxim (BDM), during IPost increased myocardial ATP and facilitated the redistribution of dystrophin to the sarcolemma. This led to reduced cardiomyocyte oncosis and infarct size, and improved the left ventricular function. The anti-oncotic effect of BDM occurred without changing the anti-apoptotic effect of IPost. The PI3K inhibitor, LY294002, prevented the phosphorylation of Akt, decreased the recovery of ATP and restoration of sarcolemmal dystrophin, and blocked the anti-oncotic and anti-apoptotic effects of IPost. Conclusions:These results suggest that the inhibition of contractile activity during IPost prevents cardiomyocyte oncosis and enhances cardioprotection through PI3K-dependent restoration of sarcolemmal dystrophin. (Circ J 2010; 74: 2393 - 2402

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Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition

Bin,

Zaobornyj,

Garces

et al. 2023

Mol Cell Biochem

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The death of myocytes occurs through different pathways, but a key point in the transition from reversible to irreversible injury is the rupture of the plasma membrane. Three major groups of structural proteins that link the extracellular and intracellular milieus and confer structural stability to the cell membrane are present in cardiac myocytes: the dystrophin-associated protein complex, the vinculinintegrin link, and the spectrin-based submembranous cytoskeleton.The objective was to determine if rIPC preserves membrane-associated cytoskeletal proteins (dystrophin and β-dystroglycan) through the inhibition of metalloproteinase type 2 (MMP-2) activity. A second objective was to describe some of the intracellular signals of the rIPC, that modify mitochondrial function and are activated during early reperfusion.Methods: Isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion (I/R). rIPC was performed by 3 cycles of ischemia/reperfusion in the lower limb (rIPC). Results: As we expected, rIPC signi cantly decreased the infarct size. rIPC induced an Akt/GSK-3b phosphorylation and the inhibition of the MPTP opening, improving mitochondrial function, increasing membrane potential, ATP production and respiratory control. I/R induced ONOOproduction, which activates MMP-2. This enzyme degrades β-dystroglycan and dystrophin and collaborates to sarcolemmal disruption. Conclusion: rIPC attenuates the breakdown of β-dystroglycan and dystrophin through the inhibition of MMP-2 activity. Furthermore, rIPC activates different intracellular pathway that involves the an Akt/Gsk3b and MPTP pore with preservation of mitochondrial function.

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Dystrophin is a possible end-target of ischemic preconditioning against cardiomyocyte oncosis during the early phase of reperfusion

Abstract: These results suggest that enhanced relocalization of dystrophin to the sarcolemma during reperfusion may be a mechanistic link between IPC-mediated improvement of mitochondrial function and its protection against oncosis during the early phase of reperfusion.

Cited by 19 publications

References 27 publications

Cytoskeletal Proteins

Cytoskeletal Proteins

Inhibition of Contractile Activity During Postconditioning Enhances Cardioprotection by Restoring Sarcolemmal Dystrophin Through Phosphatidylinositol 3-Kinase

Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition

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