Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction.
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 microL versus 128.5+/-5.7 microL; 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]-1alpha, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-alpha, interferon-gamma, 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.
Timmers
Leo
L
Department of Cardiology, University Medical Center, Utrecht, The Netherlands.
Sluijter
Joost P G
JP
van Keulen
J Karlijn
JK
Hoefer
Imo E
IE
Nederhoff
Marcel G J
MG
Goumans
Marie-Jose
MJ
Doevendans
Pieter A
PA
van Echteld
Cees J A
CJ
Joles
Jaap A
JA
Quax
Paul H
PH
Piek
Jan J
JJ
Pasterkamp
Gerard
G
de Kleijn
Dominique P V
DP
D000818:Animals; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000628:therapy; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology*; D013318:Stroke Volume; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*; D020257:Ventricular Remodeling
D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4