Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart

Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2316-23. doi: 10.1152/ajpheart.00763.2001.


The precise molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. Toll-like receptor-4 (TLR-4) engages lipopolysaccharide (LPS) and activates signaling pathways leading to the expression of proinflammatory cytokines implicated in myocardial dysfunction. We determined whether TLR-4 was necessary for LPS-induced myocardial dysfunction in vivo. The effects of LPS on left ventricular (LV) function were studied in mice with defective TLR-4 signaling (C3H/HeJ, TLR-4 deficient) and wild-type mice (C3HeB/FeJ). Mice (n = 5/group) were injected with LPS or diluent, and LV function was examined by using two-dimensional echocardiography and conductance catheters. LPS significantly decreased all indexes of LV function in wild-type mice when compared with controls; LV function was not depressed in the LPS-treated TLR-4-deficient mice relative to controls. LPS increased myocardial nitric oxide synthase-2 expression and cGMP only in wild-type mice. This study suggests that TLR-4 mediates the LV dysfunction that occurs in LPS-induced shock. Therefore, TLR-4 might be a therapeutic target for attenuating the effects of LPS on the heart.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cardiac Catheterization
  • Cyclic GMP / analysis
  • Drosophila Proteins*
  • Echocardiography, Doppler
  • Escherichia coli*
  • Female
  • Heart / physiopathology*
  • Heart Ventricles / chemistry
  • Heart Ventricles / enzymology
  • Hemodynamics
  • Lipopolysaccharides / toxicity*
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C3H
  • Mutation, Missense
  • Myocardium / enzymology
  • Nitric Oxide Synthase / analysis
  • Nitric Oxide Synthase Type II
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Signal Transduction
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Ventricular Dysfunction, Left / chemically induced*


  • Drosophila Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclic GMP