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

Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H470-9. doi: 10.1152/ajpheart.01051.2008. Epub 2008 Dec 19.


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-alpha. We observed that autophagy was increased after exposure to LPS or TNF-alpha, which is induced by LPS. The inhibition of TNF-alpha 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 H(2)O(2) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Animals, Newborn
  • Antioxidants / pharmacology
  • Autophagy / drug effects*
  • Cells, Cultured
  • Cytoprotection*
  • Enzyme Inhibitors / pharmacology
  • Glutathione / metabolism
  • Hydrogen Peroxide / metabolism
  • Imidazoles / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Transgenic
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Nitroprusside / pharmacology
  • Oxidative Stress / drug effects*
  • Pyridines / pharmacology
  • Rats
  • Signal Transduction / drug effects*
  • Sirolimus / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrphostins / pharmacology
  • omega-N-Methylarginine / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antioxidants
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • Nitric Oxide Donors
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Tyrphostins
  • AG 127
  • Nitroprusside
  • omega-N-Methylarginine
  • Nitric Oxide
  • Hydrogen Peroxide
  • Nitric Oxide Synthase
  • p38 Mitogen-Activated Protein Kinases
  • Glutathione
  • SB 203580
  • Sirolimus
  • Acetylcysteine