Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia-Reperfusion Injury

Cai, Zhejun; Manalo, Dominador J.; W, Guo; Rodríguez, E. René; Fox-Talbot, Karen; Lu, Hongyang; Zweíer, Jay L.; Semenza, Gregg L.

doi:10.1161/01.cir.0000078635.89229.8a

Cited by 507 publications

(433 citation statements)

References 32 publications

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“…12 Further, studies performed on isolated hearts have shown that EPO mediates ischemic preconditioning. 72 The kidney is protected by EPO in the setting of both ischemic and toxic injuries. [73][74][75] In ischemic injury with reperfusion, EPO prevents apoptosis of tubular epithelial cells as well as mediates intense mitotic activity of the surviving population of proximal tubular epithelial cells.…”

Section: Epo Signaling In Nervous System Cellsmentioning

confidence: 99%

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Ghezzi

Brines²

2004

Cell Death Differ

307

238

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Erythropoietin (EPO) increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In addition to this proerythroid action, results of recent studies show that systemically administered EPO is protective in vivo, in several animal models of neuronal injury. In vitro, EPO prevents neuronal apoptosis induced by a variety of stimuli. This review summarizes the neuroprotective actions of EPO and discusses the underlying mechanisms in terms of signal transduction pathways involved. The understanding of these mechanisms will help differentiate the neuroprotective actions of EPO from its role in the bone marrow.

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Section: Epo Signaling In Nervous System Cellsmentioning

confidence: 99%

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Ghezzi

Brines²

2004

Cell Death Differ

307

238

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“…Cardiac preconditioning, which has been demonstrated in many species, can be induced through a variety of methods including hypoxia/ischemia [40], anesthetics [41], glucose [42], phorbol esters [43], cannabinoids [44], and heat-stress [45]. It is assumed that these act in a unified manner and activation of PKCε is, most likely, key to this control [46].…”

Section: Two Pkcs Which Respond To Stress Pkcε In the Heartmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

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“…Hypoxic preconditioning (PC), like ischemic PC [9] can provide delayed protection against ischemia-reperfusion injury [10,11]. IH for 4 hrs with 10% O 2 induces cardioprotection illustrated by a reduction of infarct size in isolated rat heart [8].…”

Section: Introductionmentioning

confidence: 99%

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Béguin

Belaidi

Godin‐Ribuot

et al. 2007

Journal of Molecular and Cellular Cardiology

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. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2.. Journal of Molecular and Cellular Cardiology, Elsevier, 2007, 42 (2) AbstractObjective. We previously reported that acute intermittent hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of nitric oxide synthase and K ATP channels. In the present study, we investigated the role of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated p38 MAP kinase (MAPK) and extracellular signal regulated kinase (ERK1/2) using selective inhibitors of these pathways. Methods. Adult male rats were exposed to 1-min cycles of IH (10% O 2 , 40 sec) / normoxia (21% O 2 , 20 sec) during 4 hrs or to normoxic cycles. 24 hrs later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global ischemia followed by 120 min of reperfusion. Results. Compared to normoxic conditions, IH significantly reduced infarct size (22.2  2.4% vs 33.8  2.6%, p<0.05), improved coronary flow and decreased the contracture at reperfusion. When administered before sustained ischemia, chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in infarct size (36.1  4.9%) and improvement in hemodynamic parameters. In contrast, chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly, wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of SB203580 (a p38 MAPK inhibitor) and PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed infarct-sparing effect (32.2  3.4% and 33.9  2.9% respectively). In addition, 24 hrs after IH, a significant increase in p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. Conclusion. These results suggest that the delayed preconditioning induced by intermittent hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by p38 MAPK and Erk1/2.

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Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia-Reperfusion Injury

Cited by 507 publications

References 32 publications

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Protein kinase C as a stress sensor

Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

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