Inhibition of Phosphodiesterases Leads to Prevention of the Mitochondrial Permeability Transition Pore Opening and Reperfusion Injury in Cardiac H9c2 Cells

Zhou, Juan; Lee, Sungryul; McIntosh, Rachel; Shen, Xiang; Zvara, David A.; Xu, Zhelong

doi:10.1007/s10557-011-6310-z

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…mPTP is a multiprotein complex formed between the inner and outer mitochondrial membranes . mPTP opening is critical to mitochondria‐mediated apoptosis during I/R injury . The voltage‐dependent anion channel 1 (VDAC1), in the mitochondrial outer membrane, acts as a gate to control the inflow and outflow of mitochondrial metabolites and ions .…”

Section: Introductionmentioning

confidence: 99%

Long-term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: Involvement of VDAC1 downregulation

Liao

Liu

Tang

et al. 2015

Mol. Nutr. Food Res.

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Section: Introductionmentioning

confidence: 99%

Long-term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: Involvement of VDAC1 downregulation

Liao

Liu

Tang

et al. 2015

Mol. Nutr. Food Res.

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“…Therefore, morin seems to be a promising compound that may be used for preventing MIRI. A number of drugs and chemical compounds, including rosuvastatin ( 31 ), tauroursodeoxycholic acid ( 32 ), tilianin ( 33 ) and phosphodiesterases ( 34 ), have been demonstrated to prevent MIRI by inhibition of MPTP opening. Woodman et al ( 35 ) confirmed that 3′,4′-dihydroxyflavonol, a flavonoid compound, may inhibit MPTP opening and preserve mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of morin on myocardial ischemia‑reperfusion injury in rats

Liu

Miao

et al. 2018

Int J Mol Med

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Morin, a natural flavonol, exhibits antioxidative, anti-inflammatory and anti-apoptotic effects in various pathological and physiological processes. However, whether morin exerts a protective effect on myocardial ischemia-reperfusion injury (MIRI) is unknown. The present study aimed to determine the effect of morin on MIRI in cultured cardiomyocytes and isolated rat hearts, and to additionally explore the underlying mechanism. The effect of morin on the viability, lactate dehydrogenase (LDH) activity and apoptosis of H9c2 cardiomyocytes subjected to hypoxia/reoxygenation, and cardiac function and infarct size of rat hearts following ischemia/reperfusion in an animal model were measured. Furthermore, the mitochondrial permeability transition pore (MPTP) opening, mitochondrial membrane potential (ΔΨm), and the change in the expression levels of B-cell lymphoma 2 (Bcl2)-associated X protein (Bax), Bcl-2 and mitochondrial apoptosis-associated proteins following MPTP opening were also detected. The results indicated that morin treatment significantly increased cell viability, decreased LDH activity and cell apoptosis, improved the recovery of cardiac function and decreased the myocardial infarct size. Furthermore, morin treatment markedly inhibited MPTP opening, prevented the decrease of ΔΨm, and decreased the expression of cytochrome c, apoptotic protease activating factor-1, caspase-9, caspase-3 and the Bax/Bcl-2 ratio. However, these beneficial effects were reversed by treatment with atractyloside, an MPTP opener. The present study demonstrated that morin may prevent MIRI by inhibiting MPTP opening and revealed the possible mechanism of the cardioprotection of morin and its acting target. It also provided an important theoretical basis for the research on drug interventions for MIRI in clinical applications.

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“…Mitochondrial membrane potential was monitored by tetramethylrhodamine ethyl ester (TMRE) fluorescence as previously reported [19], [20]. H9c2 cells or C2C12 cells were loaded with TMRE (100 nM) 1 h before AA treatment for assessing the effects of AA on ΔΨ m or at the time of AA washout for assessing recovery of ΔΨ m from oxidant stress by AA.…”

Section: Methodsmentioning

confidence: 99%

Accelerated Recovery of Mitochondrial Membrane Potential by GSK-3β Inactivation Affords Cardiomyocytes Protection from Oxidant-Induced Necrosis

et al. 2014

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Loss of mitochondrial membrane potential (ΔΨm) is known to be closely linked to cell death by various insults. However, whether acceleration of the ΔΨm recovery process prevents cell necrosis remains unclear. Here we examined the hypothesis that facilitated recovery of ΔΨm contributes to cytoprotection afforded by activation of the mitochondrial ATP-sensitive K+ (mKATP) channel or inactivation of glycogen synthase kinase-3β (GSK-3β). ΔΨm of H9c2 cells was determined by tetramethylrhodamine ethyl ester (TMRE) before or after 1-h exposure to antimycin A (AA), an inducer of reactive oxygen species (ROS) production at complex III. Opening of the mitochondrial permeability transition pore (mPTP) was determined by mitochondrial loading of calcein. AA reduced ΔΨm to 15±1% of the baseline and induced calcein leak from mitochondria. ΔΨm was recovered to 51±3% of the baseline and calcein-loadable mitochondria was 6±1% of the control at 1 h after washout of AA. mKATP channel openers improved the ΔΨm recovery and mitochondrial calcein to 73±2% and 30±7%, respectively, without change in ΔΨm during AA treatment. Activation of the mKATP channel induced inhibitory phosphorylation of GSK-3β and suppressed ROS production, LDH release and apoptosis after AA washout. Knockdown of GSK-3β and pharmacological inhibition of GSK-3β mimicked the effects of mKATP channel activation. ROS scavengers administered at the time of AA removal also improved recovery of ΔΨm. These results indicate that inactivation of GSK-3β directly or indirectly by mKATP channel activation facilitates recovery of ΔΨm by suppressing ROS production and mPTP opening, leading to cytoprotection from oxidant stress-induced cell death.

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Inhibition of Phosphodiesterases Leads to Prevention of the Mitochondrial Permeability Transition Pore Opening and Reperfusion Injury in Cardiac H9c2 Cells

Abstract: Inhibition of PDEs prevents the mPTP opening by inactivating GSK-3β through PKA and PKG. GSK-3β is a common downstream target of PKA and PKG. Inhibition of PDEs may be a useful approach to prevent reperfusion injury.

Cited by 12 publications

References 38 publications

Long-term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: Involvement of VDAC1 downregulation

Long-term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: Involvement of VDAC1 downregulation

Protective effect of morin on myocardial ischemia‑reperfusion injury in rats

Accelerated Recovery of Mitochondrial Membrane Potential by GSK-3β Inactivation Affords Cardiomyocytes Protection from Oxidant-Induced Necrosis

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