Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers

Abstract

Background: We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers.

Methods and results: Twenty-four otherwise healthy cigarette smokers participated in a randomized double-blind, placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328 ± 748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (-11.6 ± 20 versus 6 ± 21 mg/dL), low-density lipoprotein cholesterol (-10 ± 17 versus 3 ± 21 mg/dL), and triglyceride (-39.8 ± 77 versus 13.3 ± 57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose-dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014.

Conclusions: SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers.

Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT01031108.

Keywords: SIRT1; cigarette smokers; endothelium; forearm plethysmography; platelet activation; sirtuins; vascular.

Figure 1.

Study design: schematic representation of study design. PK indicates pharmacokinetic; SCR, screening.

Figure 2.

Pharmacokinetics: mean plasma concentration–time curve following oral dosing of SRT2104 on day 1 (closed circles) and day 28 (open circles). Data presented as mean±SD.

Figure 3.

Effect of bradykinin (100, 300, 1000 pmol/min), acetylcholine (5, 10, 20 μg/min), and sodium nitroprusside (2, 4, 8 μg/min) on absolute forearm blood flow. Blue, placebo; red, SRT2104; closed circle, infused forearm blood flow; open circle, noninfused forearm blood flow. Data presented as mean±95% confidence interval.

Figure 4.

Effect of SRT2104 on markers of platelet and monocyte activation. Data presented as mean±SD. PMA indicates platelet–monocyte aggregate; Mac‐1, macrophage‐1 antigen; sCD40L, soluble CD40 ligand.