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The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans*

van der Meer, Anne J. MD¹; Scicluna, Brendon P. PhD¹; Moerland, Perry D. PhD²; Lin, Jiang PhD³; Jacobson, Eric W. MD⁴; Vlasuk, George P. PhD⁴; van der Poll, Tom MD, PhD¹

Author Information

¹Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands.

²Bioinformatics Laboratory, Department of Clinical Epidemiology, Academic Medical Center, Amsterdam, The Netherlands.

³GlaxoSmithKline, Durham, North Carolina.

⁴Sirtris, A GSK Company, Cambridge, MA.

* See also p. 1348.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by Sirtris, a GlaxoSmithKline company (NCT01014117).

Dr. Lin is employed by GlaxoSmithKline and has stock in GlaxoSmithKline (GSK). Dr. Jacobson is employed by Sirtris Pharma, a division of GSK and has stock options in GSK (previously received stock grants from GSK). Dr. Vlasuk disclosed past employment with GSK (employee of GSK at the time the work was conducted for this article) and has stock in GSK. His institution has a patent with GSK (GSK has issued patents on the compound [SRT2104] used in this study). Dr. van der Poll’s institution received grant support from Sirtris (study was supported by Sirtris). Dr. Scicluna is supported by a grant from the Center of Translational and Molecular Medicine (CTMM). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 43(6):p e199-e202, June 2015. | DOI: 10.1097/CCM.0000000000000949

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.

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The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans*