Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart

Mauricio Ibacache; Gina Sanchez; Zully Pedrozo; Felipe Galvez; Claudio Humeres; Ghislaine Echevarria; Juan Duaso; Mario Hassi; Lorena Garcia; Guillermo Díaz-Araya; Sergio Lavandero

doi:10.1016/j.bbadis.2011.12.013

Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart

Mauricio Ibacache, Gina Sanchez, Zully Pedrozo, Felipe Galvez, Claudio Humeres, Ghislaine Echevarria, Juan Duaso, Mario Hassi, Lorena Garcia, Guillermo Díaz-Araya, Sergio Lavandero

Universidad de Chile

Research output: Contribution to journal › Article › peer-review

98 Citations (Scopus)

Abstract

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α ₂-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30min of regional ischemia followed by 120min of reperfusion with dexmedetomidine before ischemia. The α ₂-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α ₂-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α ₂-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α ₂-adrenergic receptor stimulation.

Original language	English
Pages (from-to)	537-545
Number of pages	9
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1822
Issue number	4
DOIs	https://doi.org/10.1016/j.bbadis.2011.12.013
Publication status	Published - Apr 2012

Bibliographical note

Funding Information:
This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT ): Grant 1080497 (G.S.), Grant 1110346 (L.G; S.L), Postdoctoral Fellowship 3110039 (Z.P). and Fondo de Investigación Avanzada en Areas Prioritarias (FONDAP ) Grant: 15010006 (G.S., S.L.), and the Comisión Nacional de Investigación Cientifica y Tecnologica (CONICYT), Santiago, Chile .

Funding

This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT ): Grant 1080497 (G.S.), Grant 1110346 (L.G; S.L), Postdoctoral Fellowship 3110039 (Z.P). and Fondo de Investigación Avanzada en Areas Prioritarias (FONDAP ) Grant: 15010006 (G.S., S.L.), and the Comisión Nacional de Investigación Cientifica y Tecnologica (CONICYT), Santiago, Chile .

Funders	Funder number
Fondo Nacional de Desarrollo Científico y Tecnológico	1110346, 3110039, 1080497

ASJC Scopus Subject Areas

Molecular Medicine
Molecular Biology

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10.1016/j.bbadis.2011.12.013

Cite this

Ibacache, M., Sanchez, G., Pedrozo, Z., Galvez, F., Humeres, C., Echevarria, G., Duaso, J., Hassi, M., Garcia, L., Díaz-Araya, G., & Lavandero, S. (2012). Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1822(4), 537-545. https://doi.org/10.1016/j.bbadis.2011.12.013

Ibacache, M, Sanchez, G, Pedrozo, Z, Galvez, F, Humeres, C, Echevarria, G, Duaso, J, Hassi, M, Garcia, L, Díaz-Araya, G & Lavandero, S 2012, 'Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1822, no. 4, pp. 537-545. https://doi.org/10.1016/j.bbadis.2011.12.013

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abstract = "Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α 2-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30min of regional ischemia followed by 120min of reperfusion with dexmedetomidine before ischemia. The α 2-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α 2-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α 2-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α 2-adrenergic receptor stimulation.",

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note = "Funding Information: This work was supported by Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico (FONDECYT ): Grant 1080497 (G.S.), Grant 1110346 (L.G; S.L), Postdoctoral Fellowship 3110039 (Z.P). and Fondo de Investigaci{\'o}n Avanzada en Areas Prioritarias (FONDAP ) Grant: 15010006 (G.S., S.L.), and the Comisi{\'o}n Nacional de Investigaci{\'o}n Cientifica y Tecnologica (CONICYT), Santiago, Chile . ",

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AU - Humeres, Claudio

AU - Echevarria, Ghislaine

AU - Duaso, Juan

AU - Hassi, Mario

AU - Garcia, Lorena

AU - Díaz-Araya, Guillermo

AU - Lavandero, Sergio

N1 - Funding Information: This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT ): Grant 1080497 (G.S.), Grant 1110346 (L.G; S.L), Postdoctoral Fellowship 3110039 (Z.P). and Fondo de Investigación Avanzada en Areas Prioritarias (FONDAP ) Grant: 15010006 (G.S., S.L.), and the Comisión Nacional de Investigación Cientifica y Tecnologica (CONICYT), Santiago, Chile .

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N2 - Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α 2-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30min of regional ischemia followed by 120min of reperfusion with dexmedetomidine before ischemia. The α 2-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α 2-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α 2-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α 2-adrenergic receptor stimulation.

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Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

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