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.
|Number of pages||8|
|State||Published - Mar 8 2012|
ASJC Scopus subject areas
- Cell Biology