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Original Articles: Adult Cardiac

Cytokines Link Toll-Like Receptor 4 Signaling to Cardiac Dysfunction After Global Myocardial Ischemia

^a Department of Surgery, University of Colorado Denver, Denver, Colorado
^b Department of Medicine, University of Colorado Denver, Denver, Colorado
^c Department of Cardiothoracic Surgery, Sun Yat-Sen University School of Medicine, Guangzhou, China
^d Keshan Disease Research Institute, Harbin Medical University, Harbin, China

Accepted for publication January 11, 2008.

^_* Address correspondence to Dr Meng, Department of Surgery, Box C-320, University of Colorado Denver, 4200 E 9th Ave, Denver CO 80262 (Email: xianzhong.meng{at}uchsc.edu).

Background: Although Toll-like receptor 4 (TLR4) has been implicated in the myocardial injury caused by regional ischemia/reperfusion, its role in the myocardial inflammatory response and in contractile dysfunction after global ischemia/reperfusion is unclear. Cytokines, particularly tumor necrosis factor- (TNF-), contribute to the mechanism of myocardial dysfunction after global ischemia/reperfusion. We hypothesized that a TLR4-mediated cytokine cascade modulates myocardial contractile function after global ischemia/reperfusion. This study examined whether TLR4 regulates TNF- and interleukin (IL)-1β peptide production during global ischemia/reperfusion and whether TLR4 signaling influences postischemic cardiac function through TNF- and IL-1β.

Methods: Isolated hearts from wild-type mice, two strains of TLR4 mutants, TNF- knockouts, and IL-1β knockouts underwent global ischemia/reperfusion. Cardiac contractile function was analyzed, and myocardial nuclear factor-B activity and TNF- and IL-1β levels were measured.

Results: In wild-type hearts, global ischemia/reperfusion induced nuclear factor-B activation and the production of TNF- and IL-1β peptides. In TLR4-mutant hearts, these changes were significantly reduced and postischemic functional recovery was improved. Application of TNF- and IL-1β to TLR4-mutant hearts abrogated this improvement in postischemic functional recovery. Postischemic functional recovery also improved in TNF- knockout and IL-1β knockout hearts, as well as in wild-type hearts treated with TNF-binding protein or IL-1 receptor antagonist.

Conclusions: This study demonstrates that TLR4 signaling contributes to cardiac dysfunction after global ischemia/reperfusion. TLR4 signaling mediates the production of TNF- and IL-1β peptides, and these two cytokines link TLR4 signaling to postischemic cardiac dysfunction.

Related Article

Invited Commentary

Niels P. van der Kaaij and Ad J.J.C. Bogers
Ann. Thorac. Surg. 2008 85: 1685. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				N. P. van der Kaaij and A. J.J.C. Bogers Invited commentary. Ann. Thorac. Surg., May 1, 2008; 85(5): 1685 - 1685. [Full Text] [PDF]