Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn037
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Lipopolysaccharide-induced myocardial protection against ischemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism
1 Department of Surgery East Tennessee State University, Johnson City, TN 37614
2 Cardiovascular Division Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston Massachusetts, 02215
3 Department of Internal Medicine East Tennessee State University, Johnson City, TN 37614
4 Animal Model Research Center Nanjing University, Nanjing, China, 210093
5 Baker Heart Research Institute Melbourne, Victoria, Australia, 8008
Correspondence author: Chuanfu Li, M.D. Department of Surgery James H. Quillen College of Medicine East Tennessee State University P.O. Box 70575 Johnson City, TN 37614-0575 Tel 423-439-6349 FAX 423-439-6259 Email Address: Li{at}ETSU.EDU
Aim: The ability of lipopolysaccharide (LPS) pretreatment to induce cardioprotection following ischemia/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) signaling pathways. We hypothesized that activation of PI3K/Akt signaling plays a critical role in LPS-induced cardioprotection.
Methods: To evaluate this hypothesis, we pretreated mice with LPS 24 hrs before the hearts were subjected to ischemia (45 min) and reperfusion (4 hrs). We examined activation of the PI3K/Akt/GSK-3β signaling pathway. The effect of PI3K/Akt inhibition on LPS-induced cardioprotection was also evaluated.
Results: LPS pretreatment 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-pretreated mice were significantly reduced following I/R. LPS pretreatment 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 (kdAkt) transgenic mice abolished the cardioprotection induced by LPS.
Conclusions: These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.
KEYWORDS LPS; myocardium; cardioprotection; TLR/NF
B pathway; PI3K/Akt activity
Time for primary review: 24 days
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