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(Circulation. 2006;114:I-270 – I-274.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury

Akira Shimamoto, MD, PhD; Albert J. Chong, MD; Masaki Yada, MD, PhD; Shin Shomura, MD; Hiroo Takayama, MD; Ani J. Fleisig, MD; Matthew L. Agnew, MD; Craig R. Hampton, MD; Christine L. Rothnie, BS; Denise J. Spring, PhD; Timothy H. Pohlman, MD; Hideto Shimpo, MD, PhD; Edward D. Verrier, MD

From the Department of Thoracic & Cardiovascular Surgery (A.S., M.Y., H.S.), Mie University Graduate School of Medicine, Tsu, Japan; Division of Cardiothoracic Surgery (A.J.C., S.S., H.T., A.J.F., M.L.A., C.R.H., C.L.R., D.J.S., T.H.P., E.D.V.), Department of Surgery, University of Washington School of Medicine, Seattle, Wash.

Correspondence to Akira Shimamoto, Department of Thoracic & Cardiovascular Surgery, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan. E-mail jj6jdv{at}clin.medic.mie-u.ac.jp

Background— We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury.

Methods and Results— C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH₂-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-B activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0±6.4% versus 30.9±13.9%; P=0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98±0.81 versus 7.01±2.21-fold increase; P=0.020), less nuclear NF-B translocation (2.70±0.35 versus 7.75±0.60-fold increase; P=0.00007), and a decrease in cytokine expression (P<0.05).

Conclusions— We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.

Key Words: ischemia • myocardial infarction • reperfusion • signal transduction