Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3β and transcription factor β-catenin

Bergmann, Martin; Rechner, Cindy; Freund, Christian; Baurand, Anthony; Jamali, Amina El; Dietz, Rainer

doi:10.1016/j.yjmcc.2004.05.025

Cited by 63 publications

(51 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nuclear translocation of b-catenin is required for its survivalpromoting effect (Yuan et al 2005). We found in this study that both AG and UAG increase the nuclear translocation of b-catenin, which is known to inhibit apoptosis, in agreement with previous reports demonstrating that the neuroprotective effects of FGF1 (Hashimoto et al 2002) and lovastatin (Bergmann et al 2004) are dependent on the GSK-3b/ b-catenin signaling pathway. Taken together, these results suggest that the anti-apoptotic effect of AG and UAG involve a PI3K/Akt-mediated inactivation of GSK-3b and subsequent stabilization of b-catenin.…”

Section: Discussionsupporting

confidence: 92%

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

Chung¹,

Seo²,

Moon³

et al. 2008

Journal of Endocrinology

148

122

View full text Add to dashboard Cite

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An antiapoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3b (GSK-3b). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of b-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3b and stabilization of b-catenin contribute to the anti-apoptotic effects of ghrelin.

show abstract

Section: Discussionsupporting

confidence: 92%

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

Chung¹,

Seo²,

Moon³

et al. 2008

Journal of Endocrinology

148

122

View full text Add to dashboard Cite

show abstract

“…Accordingly, stabilizing the permeability transition pore in the mitochondrial membrane and reducing the production of ROS are important in preventing cellular apoptosis. Bergmann et al (21) identified that pravastatin pretreatment reduces the generation of ROS in anoxia-reoxygenation-injured myocardial cells, as well as the rate of cellular apoptosis. The results of the present study revealed that proanthocyanidins effectively inhibited the production of ROS induced by acute anoxia-reoxygenation, which subsequently inhibited apoptosis.…”

Section: B Amentioning

confidence: 99%

Protective effect of proanthocyanidins on anoxia-reoxygenation injury of myocardial cells mediated by the PI3K/Akt/GSK-3β pathway and mitochondrial ATP-sensitive potassium channel

Yin

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

“…Although the role of GSK-3β in apoptosis of cardiomyocytes has not been fully clarified, evidence to date supports its significant contribution to apoptosis induced by ischemia/ reperfusion, 69,[94][95][96] hypoxia/re-oxygenation, 97 β-adrenoceptor activation 98 and pressure overload. 99 Apoptosis by these insults was suppressed by overexpression of the adrenomedullin gene 95 or kallikrein gene 96 or treatment with statins, 97 all of which induced phosphorylation of GSK-3β.…”

Section: Role Of Gsk-3β In Apoptosis Of Cardiomyocytesmentioning

confidence: 99%

GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

Miura

Miki

2009

Circ J

131

112

View full text Add to dashboard Cite

lycogen synthase kinase-3β (GSK-3β) is a constitutively active 47-kDa Ser/Thr protein kinase that was purified more than 2 decades ago as a kinase that reduces glycogen synthase activity. However, GSK-3β is now known as a multifunctional kinase having more than 40 substrates, playing roles not only in glycogen metabolism but also cell proliferation, growth and death. [1][2][3] To properly execute its functions, GSK-3β has multiple regulatory mechanisms including phosphorylation at Ser and Tyr residues, complex formation with scaffold proteins, priming of substrates and intracellular translocation. Recently, pathophysiological roles of GSK-3β have also received attention because it is involved in common and serious diseases such as Alzheimer's disease, bipolar mood disorder, cancer and ischemia/reperfusion injury. 1,3 In the cardiovascular system, GSK-3β has major roles in glucose metabolism, 4 cardiomyocyte hypertrophy 5 and cell death. The roles of GSK-3β in hypertrophy have recently been reviewed by Sugden et al 5 , so therefore we have focused on the roles of this protein kinase in myocyte death, particularly that after ischemia/ reperfusion. We first briefly overview mechanisms of ischemia/reperfusion injury and then discuss the contribution of GSK-3β to cardiomyocyte death and manipulation of GSK-3β for myocardial protection. Mechanisms of Cardiomyocyte Necrosis During Ischemia/ReperfusionWhen myocardial blood perfusion is interrupted, for example by occluding the coronary artery, ischemic cardiomyocytes suffer from several critical intracellular events that can lead to cell necrosis and/or prime the cells to reperfusion-induced necrosis. First, intracellular level of highenergy phosphate is reduced due to oxygen deficiency. Although ischemic cardiomyocytes cease contraction within a few minutes after the onset of ischemia, adenosine triphosphate (ATP) consumption continues during ischemia mainly by mitochondrial ATPase for maintenance of mitochondrial membrane potential. 6,7 Anaerobic glycolysis supplies ATP during the early period of ischemia, but it is ultimately halted by inhibition of glyceraldehyde phosphate dehydrogenase due to accumulated H + and NADH. 7,8 Second, intracellular Na + accumulates due to Na + influx via Na + -H + exchangers and Na + channels and due to reduced Na + efflux via the Na + -K + pump. [9][10][11] This Na + overload predisposes ischemic cardiomyocytes to Ca 2+ influx by the Na + -Ca 2+ exchanger. Third, Ca 2+ influx via the Na + -Ca 2+ exchanger, reduced Ca 2+ uptake into the sarcoplasmic reticulum and reduced Ca 2+ efflux via the sarcolemmal Ca 2+ pump induce Ca 2+ overload in ischemic cardiomyocytes. 9-12 However, elevation of intracellular Ca 2+ is modest during ischemia because acidosis inhibits the Na + -Ca 2+ exchanger and cytosolic Ca 2+ is taken up by the mitochondria as long as its membrane potential is maintained by use of ATP. [9][10][11]13 Severely ischemic cardiomyocytes ultimately 'starve to death', although sarcolemmal damage by detergent actions of accumulated...

show abstract

Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3β and transcription factor β-catenin

Cited by 63 publications

References 41 publications

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

Protective effect of proanthocyanidins on anoxia-reoxygenation injury of myocardial cells mediated by the PI3K/Akt/GSK-3β pathway and mitochondrial ATP-sensitive potassium channel

GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

Contact Info

Product

Resources

About