The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans*. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: van der Meer, Anne J.; Scicluna, Brendon P.; Moerland, Perry D.; Lin, Jiang; Jacobson, Eric W.; Vlasuk, George P.; van der Poll, Tom
• Is Part Of: Critical care medicine. Volume 43:Issue 6(2015)
• Publication Date: 2015-06
• Subjects: sirtuin 1 -- blood coagulation -- clinical trial -- endotoxemia -- inflammation -- pharmaceutical preparations; Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000000949
• Languages: English
• ISSNs: 0090-3493

Abstract

Abstract : Objectives: Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans. Design: A randomized, double-blind, placebo-controlled study. Setting: An academic hospital. Subjects: Twenty-four healthy humans. Interventions: All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups ( n = 8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo. Measurements and Main Results: SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [ p < 0.05] and 80.9% [ p = 0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [ p < 0.05 vs placebo] and 77.1% [ p < 0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1 + 2 (mean peak levels 57.9% [ p < 0.05] and 64.2% [ p < 0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104. Conclusions: This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule. Abstract : Supplemental Digital Content is available in the text.