Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart.
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.
Nemoto
Shintaro
S
Department of Medicine, Houston Veterans Affairs Medical Center, Houston, Texas 77030, USA.
Vallejo
Jesus G
JG
Knuefermann
Pascal
P
Misra
Arunima
A
Defreitas
Gilberto
G
Carabello
Blase A
BA
Mann
Douglas L
DL
D000818:Animals; D006328:Cardiac Catheterization; D006152:Cyclic GMP / Q000032:analysis; D029721:Drosophila Proteins; D015150:Echocardiography, Doppler; D004926:Escherichia coli; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000737:chemistry / Q000201:enzymology; D006439:Hemodynamics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced*
D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006152:Cyclic GMP