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Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms

(2011) ANESTHESIOLOGY. 114(3). p.603-613
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Abstract
Background: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-beta-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Methods: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGC alpha 1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. Results: Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 +/- 3.4% vs. 19.8 +/- 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protectiveeffect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGC alpha(-/-)(1) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. Conclusions: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.
Keywords
MYOCARDIAL-ISCHEMIA, ISCHEMIA/REPERFUSION INJURY, DELAYED PROTECTION, REPERFUSION INJURY, INNATE IMMUNITY, KNOCKOUT MICE, TNF-ALPHA, IN-VIVO, MYD88, ENDOTOXIN

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Chicago
Wang, E, Yan Feng, Ming Zhang, Lin Zou, Yan Li, Emmanuel S Buys, Peigen Huang, Peter Brouckaert, and Wei Chao. 2011. “Toll-like Receptor 4 Signaling Confers Cardiac Protection Against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms.” Anesthesiology 114 (3): 603–613.
APA
Wang, E, Feng, Y., Zhang, M., Zou, L., Li, Y., Buys, E. S., Huang, P., et al. (2011). Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms. ANESTHESIOLOGY, 114(3), 603–613.
Vancouver
1.
Wang E, Feng Y, Zhang M, Zou L, Li Y, Buys ES, et al. Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms. ANESTHESIOLOGY. 2011;114(3):603–13.
MLA
Wang, E, Yan Feng, Ming Zhang, et al. “Toll-like Receptor 4 Signaling Confers Cardiac Protection Against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms.” ANESTHESIOLOGY 114.3 (2011): 603–613. Print.
@article{1197988,
  abstract     = {Background: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-beta-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC).
Methods: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGC alpha 1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined.
Results: Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P {\textlangle} 0.01) and reduced myocardial infarction sizes (37.2 +/- 3.4\% vs. 19.8 +/- 4.9\%, P {\textlangle} 0.01) after ischemia-reperfusion. The cardiac protectiveeffect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGC alpha(-/-)(1) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection.
Conclusions: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.},
  author       = {Wang, E and Feng, Yan and Zhang, Ming and Zou, Lin and Li, Yan and Buys, Emmanuel S and Huang, Peigen and Brouckaert, Peter and Chao, Wei},
  issn         = {0003-3022},
  journal      = {ANESTHESIOLOGY},
  keyword      = {MYOCARDIAL-ISCHEMIA,ISCHEMIA/REPERFUSION INJURY,DELAYED PROTECTION,REPERFUSION INJURY,INNATE IMMUNITY,KNOCKOUT MICE,TNF-ALPHA,IN-VIVO,MYD88,ENDOTOXIN},
  language     = {eng},
  number       = {3},
  pages        = {603--613},
  title        = {Toll-like receptor 4 signaling confers cardiac protection against ischemic injury via inducible nitric oxide synthase- and soluble guanylate cyclase-dependent mechanisms},
  url          = {http://dx.doi.org/10.1097/ALN.0b013e31820a4d5b},
  volume       = {114},
  year         = {2011},
}

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