This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/2/257    most recent CIRCRESAHA.107.158220v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Timmers, L. Articles by de Kleijn, D. P.V. Search for Related Content PubMed PubMed Citation Articles by Timmers, L. Articles by de Kleijn, D. P.V. Related Collections Congestive Remodeling Heart failure - basic studies Chronic ischemic heart disease Related Article

(Circulation Research. 2008;102:257.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction

Leo Timmers, Joost P.G. Sluijter, J. Karlijn van Keulen, Imo E. Hoefer, Marcel G.J. Nederhoff, Marie-Jose Goumans, Pieter A. Doevendans, Cees J.A. van Echteld, Jaap A. Joles, Paul H. Quax, Jan J. Piek, Gerard Pasterkamp, Dominique P.V. de Kleijn

From the Departments of Cardiology (L.T., J.P.G.S., J.K.v.K., I.E.H., M.G.J.N., M.-J.G., P.A.D., C.J.A.v.E., G.P., D.P.V.d.K.) and Nephrology and Hypertension (J.A.J.), University Medical Center, Utrecht; Department of Cardiology (L.T., J.J.P.), Academic Medical Center, Amsterdam; Interuniversity Cardiology Institute (J.P.G.S., J.K.v.K., M.G.J.N., P.A.D., D.P.V.d.K.), Utrecht; and The Netherlands Organization of Applied Scientific Research (P.H.Q.), Leiden.

Correspondence to D.P.V. de Kleijn, PhD, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail dkleijn{at}umcutrecht.nl

Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4^LPS–d mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume: 103.7±6.8 µL versus 128.5±5.7 µL; P<0.01) and preserved systolic function (ejection fraction: 28.2±3.1% versus 16.6±1.3%; P<0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4^LPS–d mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-, interferon-, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684±515 versus 7573±611; P=0.002) and matrix metalloproteinase-9 activity (76.0±14.3 versus 168.0±36.2; P=0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.

Key Words: myocardial infarction • remodeling • Toll-like receptor 4

Related Article:

Toll-Like Receptor Signaling: Defensive or Offensive for the Heart?

Masatsugu Hori and Kazuhiko Nishida
Circ. Res. 2008 102: 137-139. [Full Text] [PDF]

This article has been cited by other articles:

				E. Velot, B. Haas, F. Leonard, I. Ernens, M. Rolland-Turner, C. Schwartz, D. Longrois, Y. Devaux, and D. R. Wagner Activation of the adenosine-A3 receptor stimulates matrix metalloproteinase-9 secretion by macrophages Cardiovasc Res, November 1, 2008; 80(2): 246 - 254. [Abstract] [Full Text] [PDF]

				Y. Feng, H. Zhao, X. Xu, E. S. Buys, M. J. Raher, J. C. Bopassa, H. Thibault, M. Scherrer-Crosbie, U. Schmidt, and W. Chao Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1311 - H1318. [Abstract] [Full Text] [PDF]

				M. Hori and K. Nishida Toll-Like Receptor Signaling: Defensive or Offensive for the Heart? Circ. Res., February 1, 2008; 102(2): 137 - 139. [Full Text] [PDF]