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-B 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. IntroductionExposure to ambient particulate matter (PM) air pollution has been associated with impaired pulmonary function and increased cardiovascular disease-related mortality including inflammation and thrombosis. 1-5 Acute exposure to increased ambient fine particulate matter Ͻ 2.5 m in diameter (PM 2.5 ) was estimated to cause the premature deaths of tens of thousands of people each year in the United States. 6 Urban particulate matter (UPM) PM 2.5, one of the major air pollutants closely monitored by the US Environmental Protection Agency (EPA), is a complex mixture of substances that are directly emitted into the air from dust, soot, smoke, and combustion. 6 To protect public health, the EPA issued the current 24-hour PM 2.5 standard at 35 g/m 3 . 6 Despite the enormous health problems caused by PM 2.5 exposure, there have been few studies performed to explore the molecular mechanisms of PM 2.5 -induced lung vascular dysfunction. PM 2.5 can reach deep in the lung to the small airway and alveoli, 6 and directly cause lung inflammation and injury. [7][8][9][10][11][12][13] The pulmonary complications may lead to detrimental effects on other organs, particularly cardiovascular dysfunction such as systemic microvascular dysfunction and thrombosis. 1,2,4,5,13 A recent study demonstrated that short-term UPM exposure triggered the activation of primary hemostasis in healthy mice, with no substantial secondary hemostasis activation, leading to arterial but not venous thrombosis. 5 Whereas another study showed that short-term UPM exposure may cause activation of coagulation responses and fibrin formation in the lung. 14 Tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) play important roles in coagulation and fibrinolysis cascades, respectively. TFPI is an inhibitor of tissue factor (TF)-mediated coagulation responses. 15 PAI-1, on the other hand, is a major regulator of fibrinolysis, which functions by in...

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

“…50,51 Our observations are consistent with the protective effects of RSV on the vascular system. [45][46][47][48] Together with RSV, small-molecule activators of SIRT1 have been proposed in the treatment of type 2 diabetes, 52,53 another disease associated with PT. Therefore, polyphenols might become protective molecules against premature aging in PT neonates and associated cardiovascular risk.…”

“…2,44 SIRT1 also regulates the coagulation/inflammation axis 45 and glucose homeostasis. 46 Its downregulation has been associated with diabetes and cardiovascular diseases.…”

Air Pollution and Chronic Obstructive Airway Disease

“…The imbalance between levels and activity of MMPs and proteinase inhibitors has been associated with histone deacetylation and defi ciency of sirtuin 1 (SIRT1, a member of class III histone deacetylases). The protective role of SIRT1 was also supported in a study using exposure to ambient PM and gene defi cient mice in which lack of SIRT1 resulted in aggravated lung vascular leakage and infl ammation after PM exposure, which was correlated with increased NF-κB acetylation and activation (Wu et al 2012 ). Pertinent to air pollution induced COPD, increasing expression of SIRT1 was shown to reestablish the balance between proteinases and inhibitors.…”

Air Pollution and Epigenetics: Recent Findings

“…Lastly, experiments using knockout mice demonstrated that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. PM exposure aggravated lung vascular leakage and inflammation in Sirt1 knockout mice, and these effects were correlated with increased NF-kappaB acetylation and activation [58].…”