Cardiovascular Research Advance Access originally published online on February 11, 2008
Cardiovascular Research 2008 78(3):546-553; doi:10.1093/cvr/cvn037
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Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism
1 Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, PO Box 70575, TN 37614-0575, USA
2 Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3 Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
4 Baker Heart Research Institute, Melbourne, VIC 8008, Australia
5 Department of Internal Medicine, East Tennessee State University, Johnson City, TN 37614, USA
6 Animal Model Research Center, Nanjing University, Nanjing 210093, China
* Corresponding author. Tel: +1 423 439 6349; fax: +1 423 439 6259. E-mail address: li{at}etsu.edu
Aims: The ability of lipopolysaccharide (LPS) pre-treatment to induce cardioprotection following ischaemia/reperfusion (I/R) has been well documented; however, the mechanisms have not been fully elucidated. LPS is a Toll-like receptor 4 (TLR4) ligand. Recent evidence indicates that there is cross-talk between the TLR and phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathways. We hypothesized that activation of PI3K/Akt signalling plays a critical role in LPS-induced cardioprotection.
Methods and results: To evaluate this hypothesis, we pre-treated mice with LPS 24 h before the hearts were subjected to ischaemia (45 min) and reperfusion (4 h). We examined activation of the PI3K/Akt/GSK-3β signalling pathway. The effect of PI3K/Akt inhibition on LPS-induced cardioprotection was also evaluated. LPS pre-treatment significantly reduced infarct size (71.25%) compared with the untreated group (9.3 ± 1.58 vs. 32.3 ± 2.92%, P < 0.01). Cardiac myocyte apoptosis and caspase-3 activity in LPS-pre-treated mice were significantly reduced following I/R. LPS pre-treatment significantly increased the levels of phospho-Akt, phospho-GSK-3β, and heat shock protein 27 in the myocardium. Pharmacological inhibition of PI3K by LY294002 or genetic modulation employing kinase-defective Akt transgenic mice abolished the cardioprotection induced by LPS.
Conclusion: These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.
KEYWORDS Lipopolysaccharide; Myocardium; Cardioprotection; TLR/NF
B pathway; PI3K/Akt activity
Time for primary review: 24 days
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