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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/H470    most recent 01051.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Yuan, H. Articles by Gottlieb, R. A. Search for Related Content PubMed PubMed Citation Articles by Yuan, H. Articles by Gottlieb, R. A.

LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection

¹Bioscience Center and ²Department of Biology, San Diego State University, San Diego, California

Submitted 30 September 2008 ; accepted in final form 8 December 2008

Bacterial endotoxin lipopolysaccharide (LPS) is responsible for the multiorgan dysfunction that characterizes septic shock and is causal in the myocardial depression that is a common feature of endotoxemia in patients. In this setting the myocardial dysfunction appears to be due, in part, to the production of proinflammatory cytokines. A line of evidence also indicates that LPS stimulates autophagy in cardiomyocytes. However, the signal transduction pathway leading to autophagy and its role in the heart are incompletely characterized. In this work, we wished to determine the effect of LPS on autophagy and the physiological significance of the autophagic response. Autophagy was monitored morphologically and biochemically in HL-1 cardiomyocytes, neonatal rat cardiomyocytes, and transgenic mouse hearts after the administration of bacterial LPS or TNF-. We observed that autophagy was increased after exposure to LPS or TNF-, which is induced by LPS. The inhibition of TNF- production by AG126 significantly reduced the accumulation of autophagosomes both in cell culture and in vivo. The inhibition of p38 MAPK or nitric oxide synthase by pharmacological inhibitors also reduced autophagy. Nitric oxide or H₂O₂ induced autophagy in cardiomyocytes, whereas N-acetyl-cysteine, a potent antioxidant, suppressed autophagy. LPS resulted in increased reactive oxygen species (ROS) production and decreased total glutathione. To test the hypothesis that autophagy might serve as a damage control mechanism to limit further ROS production, we induced autophagy with rapamycin before LPS exposure. The activation of autophagy by rapamycin suppressed LPS-mediated ROS production and protected cells against LPS toxicity. These findings support the notion that autophagy is a cytoprotective response to LPS-induced cardiomyocyte injury; additional studies are needed to determine the therapeutic implications.

lipopolysaccharide; HL-1 cardiac myocyte; green fluorescent protein-microtubule-associated protein light chain 3; oxidative stress