Faculty Collaboration Database

Isoflurane inhibits cardiac myocyte apoptosis during oxidative and inflammatory stress by activating Akt and enhancing Bcl-2 expression. Anesthesiology 2005 Nov;103(5):1006-14

Date

10/27/2005

Pubmed ID

16249675

DOI

10.1097/00000542-200511000-00015

Abstract

BACKGROUND: Volatile anesthetics attenuate apoptosis. The underlying mechanisms remain undefined. The authors tested whether isoflurane reduces apoptosis in cardiomyocytes subjected to oxidative or inflammatory stress by enhancing Akt and B-cell lymphoma-2 (Bcl-2).

METHODS: Adult and neonatal rat ventricular myocytes and atrial HL-1 myocytes were exposed to hypoxia, hydrogen peroxide, or neutrophils with or without isoflurane pretreatment. The authors assessed cell damage and investigated apoptosis using mitochondrial cytochrome c release, caspase activity, and TUNEL assay. They determined expression of phospho-Akt and Bcl-2 and tested their involvement by blocking phospho-Akt with wortmannin and Bcl-2 with HA14-1.

RESULTS: Isoflurane significantly reduced the cell damage and apoptosis induced by hypoxia, H2O2, and neutrophils. Isoflurane reduced hypoxia-induced mitochondrial cytochrome c release in HL-1 cells by 45 +/- 12% and caspase activity by 28 +/- 4%; in neonatal cells, it reduced caspase activity by 43 +/- 5% and TUNEL-positive cells by 50 +/- 2%. Isoflurane attenuated H2O2-induced caspase activity in HL-1 cells by 48 +/- 16% and TUNEL-positive cells by 78 +/- 3%; in neonatal cells, it reduced caspase activity by 30 +/- 3% and TUNEL-positive cells by 32 +/- 7%. In adult cardiomyocytes exposed to neutrophils, isoflurane decreased both mitochondrial cytochrome c and caspase activity by 47 +/- 3% and TUNEL-positive cells by 25 +/- 4%. Isoflurane enhanced phospho-Akt and Bcl-2 expression. Wortmannin and HA14-1 prevented the action of isoflurane (53 +/- 8% and 54 +/- 7% apoptotic cells vs. 18 +/- 1% without blockers).

CONCLUSIONS: Isoflurane protects cardiomyocytes against apoptosis induced by hypoxia, H2O2, or activated neutrophils through Akt activation and increased Bcl-2 expression. This suggests that a reduction in apoptosis contributes to the cardioprotective effects of isoflurane.

Author List

Jamnicki-Abegg M, Weihrauch D, Pagel PS, Kersten JR, Bosnjak ZJ, Warltier DC, Bienengraeber MW

Authors

Zeljko J. Bosnjak PhD Professor in the Medicine department at Medical College of Wisconsin
Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anesthetics, Inhalation
Animals
Animals, Newborn
Apoptosis
Biotransformation
Caspases
Cell Line
Cell Separation
Cytochromes c
Dogs
Genes, bcl-2
Hydrogen Peroxide
Hypoxia
In Situ Nick-End Labeling
Inflammation
Isoflurane
L-Lactate Dehydrogenase
Male
Myocytes, Cardiac
Neutrophil Activation
Neutrophils
Oxidation-Reduction
Oxidative Stress
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley
Stimulation, Chemical
Tetrazolium Salts
Thiazoles