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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

^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-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-, 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-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-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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