Sevoflurane-induced cardioprotection depends on PKC-α activation via production of reactive oxygen species

• Published in: British journal of anaesthesia : BJA Vol. 99; no. 5; pp. 639 - 645
• Main Authors: Bouwman, R.A., Musters, R.J.P., van Beek-Harmsen, B.J., de Lange, J.J., Lamberts, R.R., Loer, S.A., Boer, C.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.2007; Oxford University Press
• Subjects: anaesthetics volatile; anaesthetics volatile, sevoflurane; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Inhalation - pharmacology; Animals; Biological and medical sciences; Calcium - physiology; cardioprotection; Enzyme Activation - drug effects; enzymes; enzymes, protein kinase C; enzymes, signal transduction; heart; heart, cardioprotection; heart, ischaemia; ischaemia; Ischemic Preconditioning, Myocardial - methods; Male; Medical sciences; Methyl Ethers - pharmacology; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; protein kinase C; Protein Kinase C-alpha - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; sevoflurane; signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Tissue Culture Techniques; Translocation, Genetic; anaesthetics volatile, sevoflurane; enzymes, protein kinase C; heart, ischaemia; heart, cardioprotection; signal transduction; enzymes, signal transduction; Volatile compound; Oxygen; Protein kinase C; ischaemia; signal transduction; Enzyme; Transferases; signal transduction; heart; Cardioprotective agent; Cardiovascular disease; sevoflurane; enzymes; protein kinase C; enzymes; Sevoflurane; Signal transduction; cardioprotection; heart; General anesthetic; Ischemia; Anesthesia; anaesthetics volatile; Halogen Organic compounds
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aem202

We previously demonstrated the involvement of the Ca2+-independent protein kinase C-δ (PKC-δ) isoform in sevoflurane-induced cardioprotection against ischaemia and reperfusion (I/R) injury. Since sevoflurane is known to modulate myocardial Ca2+-handling directly, in this study we investigated the role of the Ca2+-dependent PKC-α isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K+ (mitoK+ATP) channels, and PKC-δ. Preconditioned (15 min 3.8 vol% sevoflurane) isolated rat right ventricular trabeculae were subjected to I/R, consisting of 40 min superfusion with hypoxic, glucose-free buffer, followed by normoxic glucose-containing buffer for 60 min. After reperfusion, contractile recovery was expressed as percentage of force development before I/R. The role of PKC-α, ROS, mitoK+ATP channels, and PKC-δ was established using the following pharmacological inhibitors: Go6976 (GO; 50 nM), n-(2-mercaptopropionyl)-glycine (MPG; 300 μM), 5-hydroxydecanoic acid sodium (5HD; 100 μM), and rottlerin (ROT; 1 μM). Preconditioning of trabeculae with sevoflurane improved contractile recovery after I/R [65 (3)% (I/R + SEVO) vs 47 (3)% (I/R); n = 8; P < 0.05]. This cardioprotective effect was attenuated in trabeculae treated with GO [42 (4)% (I/R + SEVO + GO); P > 0.05 vs (I/R)]. In sevoflurane-treated trabeculae, PKC-α translocated towards mitochondria, as shown by immunofluorescent co-localization analysis. GO and MPG, but not 5HD or ROT, abolished this translocation. Sevoflurane improves post-ischaemic contractile recovery via activation of PKC-α. ROS production, but not opening of mitoK+ATP channels, precedes PKC-α translocation towards mitochondria. This study shows the involvement of Ca2+-dependent PKC-α in addition to the well-established role of Ca2+-independent PKC isoforms in sevoflurane-induced cardioprotection.