Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts

Rafiee, Parvaneh; Shi, Yang; Kong, Xiangrong; Pritchard, Kirkwood A.; Tweddell, James S.; Litwin, S. Bert; Mussatto, Kathleen A.; Jaquiss, Robert D.B.; Su, Jidong; Baker, John E.

doi:10.1161/01.cir.0000022018.68965.6d

Cited by 73 publications

(61 citation statements)

References 28 publications

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“…[31][32][33] However, in this study, the I/R ratio of the rats exposed to low barometric pressure hypoxia was significantly higher than that of the rats pretreated with 1000 ppm CO. And the activation of MAPKs, Akt, and eNOS induced by hypoxia was significantly weaker than that induced by 1000 ppm CO. In addition, I/R ratio was significantly lower in the rats pretreated with 1000 ppm CO than in those pretreated with 500 ppm CO, although the concentrations of HbCO in blood were not significantly different between the 2 groups (30.1% and 24.9% at 24 hours of inhalation, respectively).…”

Section: Discussioncontrasting

confidence: 74%

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Fujimoto

Ohno

Ayabe

et al. 2004

ATVB

139

120

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Background-Carbon monoxide (CO) is postulated to protect tissues against several types of injuries. We investigated the role of CO in amelioration of cardiac ischemia-reperfusion injury in vivo and the mechanisms involved in it. Methods and Results-Rats inhaled CO (250 ppm, 500 ppm, or 1000 ppm) for 24 hours in a chamber after myocardial ischemia-reperfusion induced by occluding the left anterior descending coronary artery for 30 minutes. Pre-exposure to 1000 ppm of CO significantly reduced the ratio of infarct areas to risk areas and suppressed the migration of macrophages and monocytes into infarct areas, and the expression of tumor necrosis factor (TNF)-␣ in the heart; however, 250 ppm, 500 ppm of CO, or low barometric pressure hypoxia (0.5 atm) did not affect them. Exposure to 1000 ppm CO resulted in the activation of p38 mitogen-activated protein kinase (p38MAPK), protein kinase B␣(Akt), endothelial nitric oxide synthase (eNOS), and cyclic guanosine monophosphate (cGMP) in the myocardium. Inhibition of p38MAPK, PI3kinase, NO, and soluble guanylate cyclase with SB203580, wortmannin, N(G)-nitro-L-arginine methyl ester (L-NAME), and methylene blue, respectively, attenuated the cytoprotection by CO. Conclusion-CO has beneficial effects on cardiac ischemia-reperfusion injury; this effect is mediated by p38MAPK pathway and Akt-eNOS pathway, including production of cGMP.

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Section: Discussioncontrasting

confidence: 74%

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Fujimoto

Ohno

Ayabe

et al. 2004

ATVB

139

120

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“…By elucidating the impact that prolonged periods of hypoxemia exert upon resistance to subsequent ischemia, we should be able to understand and improve cardioprotection in children with congenital heart defects. Recently we showed that infant human and rabbit hearts adapt to chronic hypoxemia by activation of PKC ⑀ , 1 p38 MAPK, and JNK signaling pathways (1). As chronic hypoxemia in rabbits induces changes in the heart similar to that found in humans, the rabbit may be useful to test other adaptive mechanisms thought to occur in human.…”

mentioning

confidence: 99%

“…Overexpression of mRNA for Hsp70 using gene therapy translates to increased Hsp70 protein levels that are associated with increased cardioprotection, suggesting this stress protein plays an important role in mediating resistance to myocardial ischemia (6). Adaptation to the stress of chronic hypoxia also results in increased cardioprotection (1,8). We therefore reasoned that adaptation to chronic hypoxia would result in increased expression of mRNA and subcellular redistribution of Hsp70 protein.…”

mentioning

confidence: 99%

Cellular Redistribution of Inducible Hsp70 Protein in the Human and Rabbit Heart in Response to the Stress of Chronic Hypoxia

Rafiee

Shi

Pritchard

et al. 2003

Journal of Biological Chemistry

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Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4-to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.

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“…4 Exposure of animals to chronic systemic hypoxia also induces protection against myocardial ischemia, although the mechanisms are poorly characterized. [5][6][7] Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes whose protein products mediate adaptive responses to hypoxia/ischemia, including erythropoietin (EPO), glucose transporter 1 (GLUT1), nitric oxide synthase 2 (NOS2), and vascular endothelial growth factor (VEGF). 8 HIF-1 consists of a constitutively expressed HIF-1␤ subunit and an O 2 -regulated HIF-1␣ subunit.…”

mentioning

confidence: 99%

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

et al. 2003

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Background-Preconditioning phenomena provide evidence for adaptive responses to ischemia that have important implications for treatment/prevention of myocardial infarction. Hypoxia-inducible factor 1 (HIF-1) mediates adaptive transcriptional responses to hypoxia/ischemia. Methods and Results-Exposure of wild-type mice to intermittent hypoxia resulted in protection of isolated hearts against ischemia-reperfusion injury 24 hours later. Cardiac protection induced by intermittent hypoxia was lost in Hif1a ϩ/Ϫ mice heterozygous for a knockout allele at the locus encoding HIF-1␣. Erythropoietin (EPO) mRNA expression was induced in kidneys of wild-type mice subjected to intermittent hypoxia, resulting in increased plasma EPO levels. EPO mRNA expression was not induced in Hif1a ϩ/Ϫ mice. EPO administration to rats increased functional recovery and decreased apoptosis in isolated hearts subjected to ischemia-reperfusion 24 hours later. Conclusions-Hearts isolated from rodents subjected to intermittent hypoxia or EPO administration are protected against postischemic injury. Cardiac protection induced by intermittent hypoxia is critically dependent on Hif1a gene dosage. Our data suggest that additional studies to evaluate therapeutic applications of EPO administration are warranted.

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Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts

Cited by 73 publications

References 28 publications

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Cellular Redistribution of Inducible Hsp70 Protein in the Human and Rabbit Heart in Response to the Stress of Chronic Hypoxia

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

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