title: Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure.
abstract: Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-κB acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. Our data show that PM exposure led to decreased lung KLF2 and TM expression in wild-type mice, and lung KLF2 and TM protein levels were further decreased in Sirt1 knock-out mice. Importantly, Sirt1 gene delivery inhibited TM and KLF2 down-regulation and reduced lung coagulation after PM exposure. Collectively, our studies indicate that Sirt1 functions as a suppressor of coagulation after particulate matter exposure.
authors.affiliation: Texas Lung Injury Institute, Center for Biomedical Research, University of Texas Health Science Center at Tyler, 75708, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Wu
authors.forename: Ming-Cheh
authors.initials: MC
authors.lastname: Liu
authors.forename: Mei
authors.initials: M
authors.lastname: Liang
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
mesh_terms: D000397:Air Pollution / Q000009:adverse effects; D000818:Animals; D002199:Capillary Permeability; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D015151:Immunoblotting; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D055370:Lung Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D052638:Particulate Matter; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism*
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008074:Lipoproteins; D052638:Particulate Matter; D017395:Plasminogen Activator Inhibitor 1; D018180:Thrombomodulin; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1