Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice.
Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cdelta and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p < 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.
Riad
Alexander
A
Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
Jäger
Sebastian
S
Sobirey
Meike
M
Escher
Felicitas
F
Yaulema-Riss
Aymaru
A
Westermann
Dirk
D
Karatas
Aysun
A
Heimesaat
Markus M
MM
Bereswill
Stefan
S
Dragun
Duska
D
Pauschinger
Matthias
M
Schultheiss
Heinz P
HP
Tschöpe
Carsten
C
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*
D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009320:Atrial Natriuretic Factor; D003094:Collagen; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin