Acute PKCδ inhibition limits ischaemia–reperfusion injury in the aged rat heart: Role of GSK-3β

Kostyak, John C.; Hunter, James C.; Korzick, Donna H.

doi:10.1016/j.cardiores.2006.02.009

Cited by 43 publications

(54 citation statements)

References 39 publications

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“…6), suggesting that beneficial effects of the peptide are related to biochemical inhibition of this PKCd activation mechanism. Nuclear translocation of PKCd is critical for the initiation of cytotoxic or proapoptotic signaling (Humphries et al, 2008;Pabla et al, 2011), and inhibition of PKCd nuclear translocation was reported to be cytoprotective following ischemia-reperfusion (Kostyak et al, 2006), focal cerebral ischemia (Shimohata et al, 2007), and radiation damage (Wie et al, 2014). Nuclear translocation is required for cleavage of PKCd, which may increase PKCd activity by removal of the regulatory domain (Okhrimenko et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

Mondrinos

Knight

Kennedy

et al. 2015

J Pharmacol Exp Ther

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Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-d (PKCd) as a critical regulator of the acute inflammatory response and demonstrated that PKCd inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCd is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)-conjugated PKCd inhibitory peptide (PKCd-TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery [,1% initial dose (ID)], whereas IT administration resulted in lung retention of .65% ID with minimal uptake in liver or kidney (,2% ID). IT delivery of a fluorescent-tagged (tetramethylrhodamine-PKCd-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCd-TAT at the time of CLP surgery significantly reduced PKCd activation (tyrosine phosphorylation, nuclear translocation and cleavage) and acute lung inflammation, resulting in improved lung function and gas exchange. Importantly, peptide efficacy was similar when delivered at 4 hours post-CLP, demonstrating therapeutic relevance. Conversely, spatial lung distribution and efficacy were significantly impaired at 8 hours post-CLP, which corresponded to marked histopathological progression of lung injury. These studies establish a functional connection between peptide spatial distribution, inflammatory histopathology in the lung, and efficacy of this anti-inflammatory peptide.

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Section: Discussionmentioning

confidence: 99%

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

Mondrinos

Knight

Kennedy

et al. 2015

J Pharmacol Exp Ther

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“…Fang et al 31 reported that PKC activation induces GSK-3β phosphorylation, and that PKC-δ interacts with GSK-3β in several cell lines. 31,32 in contrast, PKCε might indirectly regulate GSK through phosphatidylinositol-3-kinase (Pi3K), because the induction of a dominantnegative PKCε blocks the activity of Pi3K induced by phorbol ester and insulin. 33 Therefore, the selective PKC isoform responsible for modulating GSK-3β remains an area of interest for future studies.…”

Section: Discussionmentioning

confidence: 99%

Effets cardioprotecteurs du propofol dans des cœurs ischémiques puis reperfusés isolés chez le cobaye: rôle des canaux KATP et du GSK GSK-3β

Kamada

Kanaya

Hirata

et al. 2008

Can J Anesth/J Can Anesth

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reports of original investigations 595 CAN J ANESTH 55: 9 www.cja-jca.org September, 2008 Purpose: Propofol exerts cardioprotective effects, but the involved mechanisms remain obscure. The present study examines the cardioprotective effects of propofol and its role in cardiac function, including its effect on K ATP channel opening and the inhibition of GSK-3β activity in ischemia-reperfused hearts.Methods: Ischemia-reperfusion (I/R) was produced in isolated guinea pig hearts by stopping coronary perfusion for 25 min, followed by reperfusion. The hearts were incubated for ten minutes, with or without propofol (25 or 50 µM), or for five minutes with 500 µM 5-hydroxydecanoate (a mitochondrial K ATP channel blocker) or 30 µM HMR1098 (sarcolemmal K ATP channel blocker), followed by five minutes with 50 µM propofol before ischemia. Action potentials on the anterior epicardial surface of the ventricle were monitored using a high-resolution charge-coupled device camera system, and at five minutes after reperfusion, GSK-3β phosphorylation at the serine residue, Ser9, was examined.Results: After 35 min of reperfusion, propofol (25 and 50 µM) blunted the adverse effects of I/R and reduced infarct size (P < 0.05). In addition, prior incubation with 5-hydroxydecanoate or HMR1098 had no effect on functional recovery improved by 50 µM propofol. At five minutes after reperfusion, propofol (25 and 50 µM) shortened the duration of the action potential and increased the levels of phospho-GSK-3β (P < 0.05). Conclusions:Propofol enhanced mechanical cardiac recovery and reduced infarct size. The data further suggest that GSK-3β play an important role in propofol cardioprotective actions during coronary reperfusion, but mitochondrial K ATP channels do not. Objectif : Le propofol exerce des effets cardioprotecteurs, mais les mécanismes sous-jacents demeurent obscurs. Cette étude examine les effets cardioprotecteurs du propofol et son rôle dans la fonction cardiaque, notamment son effet sur l'ouverture du canal K ATP et l'inhibition de l'activité du GSK-3β dans des coeurs ischémiques puis reperfusés. Méthode : L'ischémie reperfusion (I/R) a été provoquée dans des coeurs isolés de cobayes en interrompant la per fusion

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“…Elevation (or preservation) of phospho-Ser9-GSK-3β level on reperfusion and anti-infarct tolerance have been observed in rat, rabbit or mouse hearts treated with ischemic preconditioning, 51,55-57 ischemic postconditioning, 48,58 bradykinin, 59 opioids, 60,61 EPO, 57,62 an adenosine A1/A2 receptor agonist, 63 an A3 receptor agonist, 64 PKC-ε activator, 65 PKC-δ inhibitor, 66 isoflurane, 67 lipopolysaccharide, 68 sildenafil, 69 xenon 70 or resveratrol. 71 GSK-3β phosphorylation by these apparently unrelated interventions is explained by the fact that GSK-3β is a substrate of multiple pro-survival protein kinases, including Akt, PKC-ε, extracellular signal-regulated kinase (ERK) and protein kinase G, and GSK-3β phosphorylation is therefore a step to which multiple protective signaling pathways converge.…”

Section: Gsk-3β and Tolerance Of Cardiomyocytes To Necrosismentioning

confidence: 99%

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

Miura

Miki

2009

Circ J

130

112

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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...

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Acute PKCδ inhibition limits ischaemia–reperfusion injury in the aged rat heart: Role of GSK-3β

Cited by 43 publications

References 39 publications

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

Effets cardioprotecteurs du propofol dans des cœurs ischémiques puis reperfusés isolés chez le cobaye: rôle des canaux KATP et du GSK GSK-3β

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

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