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

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-β-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 sGCα1(-/-), 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 protective effect 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 sGCα(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.

• Authors: E Wang, Yan Feng, Ming Zhang, Lin Zou, Yan Li, Emmanuel S Buys, Peigen Huang, Peter Brouckaert, Wei Chao
• Journal: Anesthesiology (Anesthesiology) Vol. 114 Issue 3 Pg. 603-13 (Mar 2011) ISSN: 1528-1175 [Electronic] United States
• PMID: 21270629 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Vesicular Transport
• Lipopolysaccharides
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• Nitrates
• Nitrites
• TICAM1 protein, human
• Toll-Like Receptor 4
• Nitric Oxide Synthase Type II
• Guanylate Cyclase

Topics

• Adaptor Proteins, Vesicular Transport (genetics, physiology)
• Animals
• Echocardiography
• Electrocardiography (drug effects)
• Guanylate Cyclase (physiology)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, physiology)
• Myocardial Infarction (pathology)
• Myocardial Ischemia (prevention & control)
• Myocardial Reperfusion Injury (pathology)
• Nitrates (blood)
• Nitric Oxide Synthase Type II (genetics, physiology)
• Nitrites (blood)
• Signal Transduction (physiology)
• Toll-Like Receptor 4 (physiology)