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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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Phosphorylation of ALDH2 associated with isoflurane-induced cardioprotection.A. Effects of isoflurane preconditioning with and without the ALDH2 inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on phosphorylation of ALDH2. (a) Representative of western blot analysis of the phosphorylation of ALDH2 (phos-ALDH2 top lanes) and total ALDH2 (middle lanes). β-actin (lower lanes) was used to demonstrate equal protein loading. (b) Quantification of phos-ALDH2 to the total ALDH2 from 3 independent experiments. B, C. Serum LDH and CK-MB concentrations were analyzed. D. The effects of ALDH inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on infarct area in rat hearts. (a) Representative cross-sectional slices derived from a single heart. (b) The infarct size normalized to the area at risk. Values are means ± S.E.M., n = 8 in each group. ##P<0.01 vs. the saline control group and *P<0.05, **P<0.01 vs. the corresponding control.
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pone-0052469-g002: Phosphorylation of ALDH2 associated with isoflurane-induced cardioprotection.A. Effects of isoflurane preconditioning with and without the ALDH2 inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on phosphorylation of ALDH2. (a) Representative of western blot analysis of the phosphorylation of ALDH2 (phos-ALDH2 top lanes) and total ALDH2 (middle lanes). β-actin (lower lanes) was used to demonstrate equal protein loading. (b) Quantification of phos-ALDH2 to the total ALDH2 from 3 independent experiments. B, C. Serum LDH and CK-MB concentrations were analyzed. D. The effects of ALDH inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on infarct area in rat hearts. (a) Representative cross-sectional slices derived from a single heart. (b) The infarct size normalized to the area at risk. Values are means ± S.E.M., n = 8 in each group. ##P<0.01 vs. the saline control group and *P<0.05, **P<0.01 vs. the corresponding control.

Mentions: Representative gels for the different treatment groups are shown in Figure 2Aa. Figure 2Ab summarizes the quantitative data on the ratio of phosphoALDH2 to total ALDH2, and shows that pretreatment with isoflurane prior to ischemia increased the phosphorylation of ALDH2. The ALDH2 inhibitor, cyanamide, significantly inhibited isoflurane-induced activation of ALDH2. The direct activator of ALDH2, Alda-44, substantially increased the phosphorylation of ALDH2, but did not enhance the phosphorylation of ALDH2 by isoflurane.


Isoflurane preconditioning confers cardioprotection by activation of ALDH2.

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

Phosphorylation of ALDH2 associated with isoflurane-induced cardioprotection.A. Effects of isoflurane preconditioning with and without the ALDH2 inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on phosphorylation of ALDH2. (a) Representative of western blot analysis of the phosphorylation of ALDH2 (phos-ALDH2 top lanes) and total ALDH2 (middle lanes). β-actin (lower lanes) was used to demonstrate equal protein loading. (b) Quantification of phos-ALDH2 to the total ALDH2 from 3 independent experiments. B, C. Serum LDH and CK-MB concentrations were analyzed. D. The effects of ALDH inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on infarct area in rat hearts. (a) Representative cross-sectional slices derived from a single heart. (b) The infarct size normalized to the area at risk. Values are means ± S.E.M., n = 8 in each group. ##P<0.01 vs. the saline control group and *P<0.05, **P<0.01 vs. the corresponding control.
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Related In: Results  -  Collection

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pone-0052469-g002: Phosphorylation of ALDH2 associated with isoflurane-induced cardioprotection.A. Effects of isoflurane preconditioning with and without the ALDH2 inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on phosphorylation of ALDH2. (a) Representative of western blot analysis of the phosphorylation of ALDH2 (phos-ALDH2 top lanes) and total ALDH2 (middle lanes). β-actin (lower lanes) was used to demonstrate equal protein loading. (b) Quantification of phos-ALDH2 to the total ALDH2 from 3 independent experiments. B, C. Serum LDH and CK-MB concentrations were analyzed. D. The effects of ALDH inhibitor (cyanamide), and direct activator of ALDH2 (Alda-44) on infarct area in rat hearts. (a) Representative cross-sectional slices derived from a single heart. (b) The infarct size normalized to the area at risk. Values are means ± S.E.M., n = 8 in each group. ##P<0.01 vs. the saline control group and *P<0.05, **P<0.01 vs. the corresponding control.
Mentions: Representative gels for the different treatment groups are shown in Figure 2Aa. Figure 2Ab summarizes the quantitative data on the ratio of phosphoALDH2 to total ALDH2, and shows that pretreatment with isoflurane prior to ischemia increased the phosphorylation of ALDH2. The ALDH2 inhibitor, cyanamide, significantly inhibited isoflurane-induced activation of ALDH2. The direct activator of ALDH2, Alda-44, substantially increased the phosphorylation of ALDH2, but did not enhance the phosphorylation of ALDH2 by isoflurane.

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