| First Author | Dong M | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1832 |
| Issue | 6 | Pages | 848-63 |
| PubMed ID | 23474308 | Mgi Jnum | J:202422 |
| Mgi Id | MGI:5519007 | Doi | 10.1016/j.bbadis.2013.02.023 |
| Citation | Dong M, et al. (2013) Chronic Akt activation attenuated lipopolysaccharide-induced cardiac dysfunction via Akt/GSK3beta-dependent inhibition of apoptosis and ER stress. Biochim Biophys Acta 1832(6):848-63 |
| abstractText | Sepsis is characterized by systematic inflammation and contributes to cardiac dysfunction. This study was designed to examine the effect of protein kinase B (Akt) activation on lipopolysaccharide-induced cardiac anomalies and underlying mechanism(s) involved. Mechanical and intracellular Ca(2)(+) properties were examined in myocardium from wild-type and transgenic mice with cardiac-specific chronic Akt overexpression following LPS (4 mg/kg, i.p.) challenge. Akt signaling cascade (Akt, phosphatase and tensin homologue deleted on chromosome ten, glycogen synthase kinase 3 beta), stress signal (extracellular-signal-regulated kinases, c-Jun N-terminal kinases, p38), apoptotic markers (Bcl-2 associated X protein, caspase-3/-9), endoplasmic reticulum (ER) stress markers (glucose-regulated protein 78, growth arrest and DNA damage induced gene-153, eukaryotic initiation factor 2alpha), inflammatory markers (tumor necrosis factor alpha, interleukin-1beta, interleukin-6) and autophagic markers (Beclin-1, light chain 3B, autophagy-related gene 7 and sequestosome 1) were evaluated. Our results revealed that LPS induced marked decrease in ejection fraction, fractional shortening, cardiomyocyte contractile capacity with dampened intracellular Ca(2)(+) release and clearance, elevated reactive oxygen species (ROS) generation and decreased glutathione and glutathione disulfide (GSH/GSSG) ratio, increased ERK, JNK, p38, GRP78, Gadd153, eIF2alpha, BAX, caspase-3 and -9, downregulated B cell lymphoma 2 (Bcl-2), the effects of which were significantly attenuated or obliterated by Akt activation. Akt activation itself did not affect cardiac contractile and intracellular Ca(2)(+) properties, ROS production, oxidative stress, apoptosis and ER stress. In addition, LPS upregulated levels of Beclin-1, LC3B and Atg7, while suppressing p62 accumulation. Akt activation did not affect Beclin-1, LC3B, Atg7 and p62 in the presence or absence of LPS. Akt overexpression promoted phosphorylation of Akt and GSK3beta. In vitro study using the GSK3beta inhibitor SB216763 mimicked the response elicited by chronic Akt activation. Taken together, these data showed that Akt activation ameliorated LPS-induced cardiac contractile and intracellular Ca(2)(+) anomalies through inhibition of apoptosis and ER stress, possibly involving an Akt/GSK3beta-dependent mechanism. |
