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.
Highlights
Acute myocardial infarction (AMI) is responsible for the death of millions of persons worldwide each year [1]
Regional myocardial ischemia for 40 min by left anterior descending (LAD) ligation followed by 120 min of reperfusion markedly increased the leakage of Lactate dehydrogenase (LDH) (Figure 1A) and creatine kinase-MB (CK-MB) (Figure 1B) compared to sham controls
Figure 2Ab summarizes the quantitative data on the ratio of phosphoALDH2 to total Aldehyde dehydrogenase 2 (ALDH2), and shows that pretreatment with isoflurane prior to ischemia increased the phosphorylation of ALDH2
Summary
Acute myocardial infarction (AMI) is responsible for the death of millions of persons worldwide each year [1]. Murry et al demonstrated that a succession of short periods of myocardial ischemia and reperfusion prior to the continuous maintenance of coronary reperfusion protects the myocardium against subsequent prolonged ischemic insults, which has been termed ‘ischemic preconditioning’ (IPC) [2]. This phenomenon is achieved by several pharmacological agents, including volatile anesthetics. APC has been shown to reduce infarct size, and attenuate contractile dysfunction and serum CK-MB concentration caused by myocardial ischemia. Mechanisms reported to date involve inhibition of mitochondrial permeability transition pore (mPTP) opening [9], the activation of kinases such as protein kinase C (PKC) [10,11], the generation of reactive oxygen species (ROS) [12,13], and opening of adenosine triphosphate-sensitive potassium channels (KATP) [3,14,15]
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