title: Atrial endothelial impairment through Toll-like receptor 4 signaling causes atrial thrombogenesis.
abstract: Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
authors.affiliation: Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Katoh
authors.forename: Shintaro
authors.initials: S
authors.lastname: Honda
authors.forename: Tetsu
authors.initials: T
authors.lastname: Watanabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ishino
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kitahara
authors.forename: Akira
authors.initials: A
authors.lastname: Funayama
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Netsu
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Sadahiro
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D018834:Chaperonin 60 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; C060293:HSPD1 protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases