Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism

• Published in: Cardiovascular research Vol. 78; no. 3; pp. 546 - 553
• Main Authors: Ha, Tuanzhu, Hua, Fang, Liu, Xiang, Ma, Jing, McMullen, Julie R., Shioi, Tetsuo, Izumo, Seigo, Kelley, Jim, Gao, Xiag, Browder, William, Williams, David L., Kao, Race L., Li, Chuanfu
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-06-2008
• Subjects: Animals; Apoptosis - drug effects; Cardioprotection; Caspase 3 - metabolism; Chromones - pharmacology; Disease Models, Animal; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heat-Shock Proteins - metabolism; HSP27 Heat-Shock Proteins; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Transgenic; Morpholines - pharmacology; Myocardial Infarction - enzymology; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocardium; Myocardium - enzymology; Myocardium - pathology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI3K/Akt activity; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; TLR/NFκB pathway; TLR/NFκB pathway; Lipopolysaccharide; Myocardium; Cardioprotection; PI3K/Akt activity
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn037

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.