Cardiovascular Effects of a Novel SIRT1 Activator, SRT2104, in Otherwise Healthy Cigarette Smokers

Abstract

BackgroundWe examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers.Methods and ResultsTwenty‐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.ConclusionsSRT2104 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 Registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT01031108.

Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease

“…Interestingly, muscle 31P magnetic resonance spectroscopy data were consistent with increased mitochondrial oxidative phosphorylation [168]. An improved lipid profile was also demonstrated with SRT2104 in otherwise healthy cigarette smokers, without demonstrable differences in vascular or platelet function [169]. Finally, treatment with SRT2104 did not result in improved glucose or insulin control after 28 days of therapy in patients with T2DM ( Table 6) although this selective activator of SIRT1 improved glucose homeostasis and increased insulin sensitivity in animal models [170].…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…In this regard, clinical evaluation of SIRT1 pharmacological activator, SRT1720, SRT3025, SRT2104, and SRT501, resulted in prevented metabolic diseases, decreased atherosclerotic plaque formation, ameliorated lipid profile of cigarette smokers, and improved glucose tolerance in type 2 diabetic patients (14,68,105,125,126,184).…”

Sirtuins in vascular diseases: Emerging roles and therapeutic potential

“…Multiple regulatory mechanisms are 595 known to take part to the signal transduction pathway responsible for 596 SIRT1 regulation in the endothelial dysfunction during altered glucose 597 homeostasis [129]. Indeed, modulation of SIRT1 can be achieved by reg- [130] reported that in a randomized double-blind, placebo-controlled 633 crossover trial, the treatment of twenty-four healthy cigarette smokers 634 with SRT2104 was associated with an 11% mean reduction in serum 635 LDL cholesterol concentrations, but without demonstrable differences inflammation in human dermal microvascular endothelial cells, PLoS One 6 (2011)…”