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Isoflurane preconditioning confers cardioprotection by activation of ALDH2.

Lang XE, Wang X, Zhang KR, Lv JY, Jin JH, Li QS - PLoS ONE (2013)

Bottom Line: Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide.Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2.In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, The First Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China.

ABSTRACT
The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury.

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Hypothetical scheme demonstrate that the phosphorylation of ALDH2 through mitochondrial translocation of PKCε plays an important role in the cardioprotection of isoflurane preconditioning in myocardium I/R injury.Ischemic preconditioning/postconditioning and pharmacological agents result in the activation of the RISK pathway, which lead to the phosphorylation and mitochondrial translocation of PKCε.
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pone-0052469-g006: Hypothetical scheme demonstrate that the phosphorylation of ALDH2 through mitochondrial translocation of PKCε plays an important role in the cardioprotection of isoflurane preconditioning in myocardium I/R injury.Ischemic preconditioning/postconditioning and pharmacological agents result in the activation of the RISK pathway, which lead to the phosphorylation and mitochondrial translocation of PKCε.

Mentions: In summary, our results demonstrate that isoflurane preconditioning increased the phosphorylation of mitochondrial ALDH2 which was mediated by mitochondrial PKCε and is required for cardiac protection against I/R (Figure 6). This work suggests a possible mechanism by which isoflurane can access cytoprotective substrates located within the mitochondria to confer cardioprotection [49]. Our data provide an insight into the mitochondrial-dependent basis of isoflurane-induced, and PKCε and ALDH2-mediated protection against cardiac ischemia, in vivo and in vitro [19]. The current study extends our understanding of APC cardiac protection, which is relevant for extrapolation to the clinic.


Isoflurane preconditioning confers cardioprotection by activation of ALDH2.

Lang XE, Wang X, Zhang KR, Lv JY, Jin JH, Li QS - PLoS ONE (2013)

Hypothetical scheme demonstrate that the phosphorylation of ALDH2 through mitochondrial translocation of PKCε plays an important role in the cardioprotection of isoflurane preconditioning in myocardium I/R injury.Ischemic preconditioning/postconditioning and pharmacological agents result in the activation of the RISK pathway, which lead to the phosphorylation and mitochondrial translocation of PKCε.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585331&req=5

pone-0052469-g006: Hypothetical scheme demonstrate that the phosphorylation of ALDH2 through mitochondrial translocation of PKCε plays an important role in the cardioprotection of isoflurane preconditioning in myocardium I/R injury.Ischemic preconditioning/postconditioning and pharmacological agents result in the activation of the RISK pathway, which lead to the phosphorylation and mitochondrial translocation of PKCε.
Mentions: In summary, our results demonstrate that isoflurane preconditioning increased the phosphorylation of mitochondrial ALDH2 which was mediated by mitochondrial PKCε and is required for cardiac protection against I/R (Figure 6). This work suggests a possible mechanism by which isoflurane can access cytoprotective substrates located within the mitochondria to confer cardioprotection [49]. Our data provide an insight into the mitochondrial-dependent basis of isoflurane-induced, and PKCε and ALDH2-mediated protection against cardiac ischemia, in vivo and in vitro [19]. The current study extends our understanding of APC cardiac protection, which is relevant for extrapolation to the clinic.

Bottom Line: Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide.Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2.In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, The First Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China.

ABSTRACT
The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury.

Show MeSH
Related in: MedlinePlus