N-n-Butyl haloperidol iodide protects against hypoxia/reoxygenation-induced cardiomyocyte injury by modulating protein kinase C activity

Wang, Jinzhi; Cai, Congyi; Zhang, Yanmei; Zheng, Jinhong; Chen, Yicun; Li, Weiqiu; Shi, Guo‐Ming

doi:10.1016/j.bcp.2010.01.021

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…We found in one previous study that H/R could induce PKC α translocation from soluble fraction to particulate fraction in cardiomyocytes [8]. In the present study, we also found that H/R could activate PKC α by increasing its phosphorylation.…”

Section: Discussionsupporting

confidence: 86%

“…These results indicate that calcium antagonists can affect cell function in ways other than blockage of calcium channels and affecting intracellular calcium levels. Our preliminary results also showed that F 2 , a new L-type calcium antagonist, can not only activate calcium-independent PKC ε through translocation in rat cardiomyocytes at the H/R stimulation and protect cardiomyocytes but also protect rat coronary endothelial cells, which do not have L-type calcium channels, from H/R injury [6, 8–11]. We therefore have reason to speculate that F 2 can protect myocardial cells from H/R injury in an extracellular-calcium-independent manner.…”

Section: Discussionmentioning

confidence: 92%

“…Further analysis has shown that F 2 is able to inhibit Egr-1 expression through suppression of the H/R-induced classical calcium-dependent PKC α translocation/activation. However, it can also activate calcium-independent PKC ε translocation/activation to protect cardiomyocytes from sustaining H/R injury [8]. In addition, in cardiac microvascular endothelial cells, which do not have L-type calcium channels, F 2 still has a protective effect against H/R injury [6, 9–11].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms

Zhang

Chen

Zhong

et al. 2013

Oxidative Medicine and Cellular Longevity

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N-n-butyl haloperidol iodide (F2) has been shown to antagonize myocardial ischemia/reperfusion injury by blocking calcium channels. This study explores the biological functions of ERK pathway in cardiomyocytes hypoxia/reoxygenation injury and clarifies the mechanisms by which F2 ameliorates cardiomyocytes hypoxia/reoxygenation injury through the extracellular-calcium-dependent and -independent ERK1/2-related pathways. In extracellularcalcium-containing hypoxia/reoxygenation cardiomyocytes, PKCα and ERK1/2 were activated, Egr-1 protein level and cTnI leakage increased, and cell viability decreased. The ERK1/2 inhibitors suppressed extracellular-calcium-containing-hypoxia/reoxygenation-induced Egr-1 overexpression and cardiomyocytes injury. PKCα inhibitor downregulated extracellularcalcium-containing-hypoxia/reoxygenation-induced increase in p-ERK1/2 and Egr-1 expression. F2 downregulated hypoxia/reoxygenation-induced elevation of p-PKCα, p-ERK1/2, and Egr-1 expression and inhibited cardiomyocytes damage. The ERK1/2 and PKCα activators antagonized F2's effects. In extracellular-calcium-free-hypoxia/reoxygenation cardiomyocytes, ERK1/2 was activated, LDH and cTnI leakage increased, and cell viability decreased. F2 and ERK1/2 inhibitors antagonized extracellular-calcium-free-hypoxia/reoxygenation-induced ERK1/2 activation and suppressed cardiomyocytes damage. The ERK1/2 activator antagonized F2's above effects. F2 had no effect on cardiomyocyte cAMP content or PKA and Egr-1 expression. Altogether, ERK activation in extracellular-calcium-containing and extracellular-calcium-free hypoxia/reoxygenation leads to cardiomyocytes damage. F2 may ameliorate cardiomyocytes hypoxia/reoxygenation injury by regulating the extracellular-calcium-dependent PKCα/ERK1/2/Egr-1 pathway and through the extracellular-calcium-independent ERK1/2 activation independently of the cAMP/PKA pathway or Egr-1 overexpression.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms

Zhang

Chen

Zhong

et al. 2013

Oxidative Medicine and Cellular Longevity

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“…We demonstrated in this study that F 2 dose-dependently suppressed apoptosis in CMECs subjected to H/R injury as evidenced by TUNEL assay, flow cytometric analysis and downregulated caspase-3 activity. Similar studies in cultured neonatal rat cardiomyocytes also showed that F 2 exerted an anti-apoptotic effect against H/R injury via inhibiting protein kinase α [33]. This suggests that the key role for F 2 in endothelial H/R injury probably is its anti-apoptotic role.…”

Section: Discussionmentioning

confidence: 62%

N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells

Wang

Zhong

et al. 2016

Oncotarget

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Endothelial cells are highly sensitive to hypoxia and contribute to myocardial ischemia/reperfusion injury. We have reported that N-n-butyl haloperidol iodide (F2) can attenuate hypoxia/reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs). However, the molecular mechanisms remain unclear. Neonatal rat CMECs were isolated and subjected to H/R. Pretreatment of F2 leads to a reduction in H/R injury, as evidenced by increased cell viability, decreased lactate dehydrogenase (LDH) leakage and apoptosis, together with enhanced AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1) phosphorylation in H/R ECs. Blockade of AMPK with compound C reversed F2-induced inhibition of H/R injury, as evidenced by decreased cell viability, increased LDH release and apoptosis. Moreover, compound C also blocked the ability of F2 to reduce H/R-induced reactive oxygen species (ROS) generation. Supplementation with the ROS scavenger N-acetyl-L-cysteine (NAC) reduced ROS levels, increased cell survival rate, and decreased both LDH release and apoptosis after H/R. In conclusion, our data indicate that F2 may mitigate H/R injury by stimulating LKB1/AMPK signaling pathway and subsequent suppression of ROS production in CMECs.

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“…Hypoxia/reoxygenation model was established according to the methods previously described [15], [16], [17], [18], [19], [20], [21] with some modifications. After 48–72 h, when the neonatal cardiomyocytes of mice were cultured to 70% confluence in appropriate culture dishes, they were pre-starved using M199 medium without fetal bovine serum for 12 h. Then hypoxia was induced by replacing the initial culture medium with DMEM without glucose and serum, which was preflushed with a gas mixture (95% N 2 and 5%CO 2 ) for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Lycopene Protects against Hypoxia/Reoxygenation-Induced Apoptosis by Preventing Mitochondrial Dysfunction in Primary Neonatal Mouse Cardiomyocytes

Yue

Yiu

et al. 2012

PLoS ONE

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BackgroundHypoxia/reoxygenation(H/R)-induced apoptosis of cardiomyocytes plays an important role in myocardial injury. Lycopene is a potent antioxidant carotenoid that has been shown to have protective properties on cardiovascular system. The aim of the present study is to investigate the potential for lycopene to protect the cardiomyocytes exposed to H/R. Moreover, the effect on mitochondrial function upon lycopene exposure was assessed.Methods and FindingsPrimary cardiomyocytes were isolated from neonatal mouse and established an in vitro model of H/R which resembles ischemia/reperfusion in vivo. The pretreatment of cardiomyocytes with 5 µM lycopene significantly reduced the extent of apoptosis detected by TUNEL assays. To further study the mechanism underlying the benefits of lycopene, interactions between lycopene and the process of mitochondria-mediated apoptosis were examined. Lycopene pretreatment of cardiomyocytes suppressed the activation of the mitochondrial permeability transition pore (mPTP) by reducing the intracellular reactive oxygen species (ROS) levels and inhibiting the increase of malondialdehyde (MDA) levels caused by H/R. Moreover, the loss of mitochondrial membrane potential, a decline in cellular ATP levels, a reduction in the amount of cytochrome c translocated to the cytoplasm and caspase-3 activation were observed in lycopene-treated cultures.ConclusionThe present results suggested that lycopene possesses great pharmacological potential in protecting against H/R-induced apoptosis. Importantly, the protective effects of lycopene may be attributed to its roles in improving mitochondrial function in H/R-treated cardiomyocytes.

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N-n-Butyl haloperidol iodide protects against hypoxia/reoxygenation-induced cardiomyocyte injury by modulating protein kinase C activity

Cited by 15 publications

References 39 publications

N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms

N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms

N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells

Lycopene Protects against Hypoxia/Reoxygenation-Induced Apoptosis by Preventing Mitochondrial Dysfunction in Primary Neonatal Mouse Cardiomyocytes

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