The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway

Li, Yuzhen; Ge, Xinlan; Li, Xiuhua

doi:10.1007/s10495-008-0296-4

Cited by 40 publications

(28 citation statements)

References 31 publications

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“…Here we showed that cardiomyocytes underwent apoptosis on a large scale during I/R injury. TUNEL data revealed that apoptosis was dramatically increased in hearts subjected to I/R, which was consistent with previous experimental and clinical studies [25,26]. In present study, administration of JWH133 significantly reduced not only the infarct size but also apoptosis induced by myocardial I/R.…”

Section: Discussionsupporting

confidence: 92%

Activation of Cannabinoid Type 2 Receptor by JWH133 Protects Heart Against Ischemia/Reperfusion-Induced Apoptosis

Wang

Zhang

et al. 2013

Cell Physiol Biochem

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Background: Cannabinoid type 2 (CB2) receptor agonists can protect myocardium against ischemia/reperfusion (I/R) injury although the underlying mechanism remains unclear. Here we report the antiapoptotic effect of CB2 receptor agonist, JWH133, during myocardial ischemia/reperfusion injury and potential underlying mechanisms. Methods: Ischemia was performed by blocking left coronary artery of rat for 30 min. After ischemia for 30 min, the rat heart was reperfused for 120 min by loosing the ligation of blocking left coronary artery. JWH133 (20 mg/kg), a CB2 receptor selective agonist, or vehicles were injected intravenously 5 minutes before ischemia. Infarct size of myocardium was assessed by histological stain, myocardial apoptosis index (AI) was determined by TUNEL, and mitochondrial membrane potential (∆Ψm) was measured by flow cytometry. Western blots were performed to measure the cytochrome c release, cleaved caspase 3, cleaved caspase 9 and PI3K/Akt kinase phosphorylation. Results: JWH133 significantly reduced the infarct size and AI of myocardium suffering I/R compared to vehicle-treated group. Further mechanistic study revealed that activation of CB2 receptor by JWH133 inhibited the loss of ΔΨm, reduction of the cleaved caspases-3 and -9, release of mitochondrial cytochrome c to the cytosol, and increase of phosphorylated Akt. These JWH133-mediated effects could be totally abrogated by PI3K inhibitor wortmanin or CB2 receptor antagonist AM630. Conclusion: Our results demonstrate that activation of CB2 receptor by JWH133 prevent apoptosis during ischemia/reperfusion through inhibition of the intrinsic mitochondria-mediated apoptotic pathway and involvement of the PI3K/Akt signal pathway.

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Section: Discussionsupporting

confidence: 92%

Activation of Cannabinoid Type 2 Receptor by JWH133 Protects Heart Against Ischemia/Reperfusion-Induced Apoptosis

Wang

Zhang

et al. 2013

Cell Physiol Biochem

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“…ARC has been shown to block apoptotic cascades in hearts (Li et al 2009). The anti-apoptotic activity of ARC depends on its phosphorylation state (Tan et al 2008), which is a balance between the effects of CK2 and the dephosphorylation by calcineurin (Li et al 2002;Zhang and Herman 2006).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Protects Cardiomyocytes from Myocardial Ischemia-Reperfusion Injury by Enhancing Phosphorylation of Apoptosis Repressor with Caspase Recruitment Domain

Yao

Tan

et al. 2012

Tohoku J. Exp. Med.

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Hydrogen sulfide (H 2 S) displays an anti-apoptotic activity against myocardial ischemia reperfusion (MIR). Apoptosis repressor with caspase recruitment domain (ARC) is constitutively expressed in the heart and inhibits cell apoptosis when it is phosphorylated. Here, we investigated whether H 2 S could inhibit apoptosis by affecting ARC phosphorylation using cultured rat cardiomyocytes and a rat model of MIR. Primary cardiomyocytes were prepared from hearts of newborn rats and were pre-incubated with NaHS, a donor of H 2 S, for 60 min. Cardiomyocytes were subjected to hypoxia for 4 h, followed by reoxygenation for 2 h. The hypoxia and subsequent reoxygenation (H/R) significantly induced cell apoptosis, increased expression levels of Fas and FasL proteins, enhanced release of cytochrome c from mitochondria, and elevated caspase-3 activity, while H/R reduced ARC phosphorylation and increased the activity of calcineurin that dephosphorylates ARC. Pre-incubation with NaHS significantly attenuated the above effects through promoting ARC phosphorylation by reducing calcineurin activity and by increasing the activity of protein kinase casein kinase II (CK2) that phosphorylates ARC. In fact, TBB, a specific inhibitor of CK2, abolished the effects of NaHS. In rats undergoing MIR, NaHS significantly reduced the myocardial infarct size, cell apoptosis, calcineurin activity, and the expression levels of Fas, FasL and cleaved caspase-3 proteins, while NaHS increased ARC phosphorylation. In contrast, DL-propargylglycine, an inhibitor of cystathionine γ-lyase, the main enzyme for H 2 S production in hearts, showed opposite effects to NaHS. The results indicate that H 2 S inhibits apoptosis of cardiomyocytes induced by MIR through enhancing ARC phosphorylation.

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“…The preparation of mitochondria and cytosolic fractions was obtained by the method described by Li et al [10] with some modifications. Briefly, left ventricular myocardium was minced and homogenized in ice-cold isolation medium.…”

Section: Detection Of Mptp Opening and Cyt -C Release In Cytosolmentioning

confidence: 99%

Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

Chen

Zhang²,

Liu³

et al. 2016

Cell Physiol Biochem

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Background: The purpose of this study was to determine whether c-jun NH₂ amino-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK) were involved in morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of the following groups. Hearts in the time control (TC) group were constantly perfused for 105min. Hearts in the ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. Anisomycin (an activator of JNK/p38 kinases) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. Mitochondria and cytosolic proteins were prepared to detect mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) respectively. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of anisomycin. I/R significantly increased the phosphorylation of JNK and p38 kinases, mitochondrial permeability transition (MPT) opening and Cyt-c release, while these effects were partly abolished by MpostC. The inhibitory effects of MpostC on the phosphorylation of JNK/p38 kinases, MPT opening and Cyt-c release were totally reversed by Anisocycin, which, used individually, did not show any influence on perfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against reperfusion injury via inhibiting JNK/p38 MAPKs and mitochondrial permeability transition pores signaling pathways.

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The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway

Abstract: Our data for the first time demonstrate that ARC plays an essential role in mediating the cardioprotective effect of postconditioning against apoptosis initiated by the mitochondrial pathway.

Cited by 40 publications

References 31 publications

Activation of Cannabinoid Type 2 Receptor by JWH133 Protects Heart Against Ischemia/Reperfusion-Induced Apoptosis

Activation of Cannabinoid Type 2 Receptor by JWH133 Protects Heart Against Ischemia/Reperfusion-Induced Apoptosis

Hydrogen Sulfide Protects Cardiomyocytes from Myocardial Ischemia-Reperfusion Injury by Enhancing Phosphorylation of Apoptosis Repressor with Caspase Recruitment Domain

Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

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