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J Thorac Cardiovasc Surg 2004;128:170-179
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart

Albert J. Chong, MDa, Akira Shimamoto, MD, PhDa, Craig R. Hampton, MDa, Hiroo Takayama, MDa, Denise J. Spring, PhDa, Christine L. Rothnie, BSa, Masaki Yada, MDb, Timothy H. Pohlman, MDa,*, Edward D. Verrier, MDa

a Division of Cardiothoracic Surgery, Department of Surgery, The University of Washington, Seattle, Wash, USA
b Department of Thoracic and Cardiovascular Surgery, Mie University, Tsu, Japan

Received for publication June 17, 2003; revisions received October 17, 2003; revisions received November 5, 2003; accepted for publication December 2, 2003.

* Address for reprints: Timothy H. Pohlman, MD, Department of Surgery, Division of Cardiothoracic Surgery, University of Washington, Box 356310, 1959 NE Pacific St, Seattle, WA 98195, USA
tpohlman{at}u.washington.edu

BACKGROUND: Restoration of blood flow to the ischemic heart may paradoxically exacerbate tissue injury (ischemia/reperfusion injury). Toll-like receptor 4, expressed on several cell types, including cardiomyocytes, is a mediator of the host inflammatory response to infection. Because ischemia/reperfusion injury is characterized by an acute inflammatory reaction, we investigated toll-like receptor 4 activation in a murine model of regional myocardial ischemia/reperfusion injury. We used C3H/HeJ mice, which express a nonfunctional toll-like receptor 4, to assess the pertinence of this receptor to tissue injury after reperfusion of ischemic myocardium.

METHODS: Wild-type mice (C3H/HeN) or toll-like receptor 4 mutant mice (C3H/HeJ) were subjected to 60 minutes of regional myocardial ischemia followed by 2 hours of reperfusion. At the end of reperfusion, the area at risk and the myocardial infarct size were measured as the end point of myocardial ischemia/reperfusion injury. Myocardial mitogen-activated protein kinase activation was measured by Western blotting, and nuclear translocation of nuclear factor-{kappa}B and activator protein-1 was determined by electrophoretic mobility shift assay. Ischemia/reperfusion–injured myocardium was also assessed by ribonuclease protection assay for expression of inflammatory mediators (tumor necrosis factor-{alpha}, interleukin-1ß, monocyte chemotactic factor-1, and interleukin-6).

RESULTS: The area at risk was similar for all groups after myocardial ischemia/reperfusion injury. There was a 40% reduction in infarct size (as a percentage of the area at risk) in C3H/HeJ mice compared with C3H/HeN mice (P = .001). Within the myocardium, significant activation of c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase was observed in both strains after ischemia and during reperfusion as compared with an absence of mitogen-activated protein kinase activation during sham operations; however, c-Jun N-terminal kinase activity, but not p38 or extracellular signal-regulated kinase activity, was significantly reduced in C3H/HeJ mice (P < .05). In both groups, nuclear factor-{kappa}B and activator protein-1 nuclear translocation occurred in the myocardium during myocardial ischemia/reperfusion injury, but, by densitometric analysis, nuclear translocation of nuclear factor-{kappa}B and activator protein-1 was significantly decreased in C3H/HeJ mice compared with C3H/HeN mice. Interleukin-1ß, monocyte chemotactic factor-1, and interleukin-6 were detectable in reperfused ischemic myocardium but were not detected in sham-operated myocardium; the expression of each of these mediators was significantly decreased in the myocardial tissue of C3H/HeJ mice when compared with expression in the control C3H/HeN mouse strain.

CONCLUSIONS: Our data suggest that toll-like receptor 4 may mediate, at least in part, myocardial ischemia/reperfusion injury. Inhibition of toll-like receptor 4 activation may be a potential therapeutic target to attenuate ischemia/reperfusion-induced tissue damage in the clinical setting.




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