Description: Oxidative and carbonyl stress is increased in lungs of smokers and patients with chronic obstructive pulmonary disease (COPD), as well as in cigarette smoke (CS)-exposed rodent lungs. We previously showed that sirtuin1 (SIRT1), an antiaging protein, is reduced in lungs of CS-exposed mice and patients with COPD and that SIRT1 attenuates CS-induced lung inflammation and injury. It is not clear whether SIRT1 protects against CS-induced lung oxidative stress. Therefore, we determined the effect of SIRT1 on lung oxidative stress and antioxidants in response to CS exposure using loss- and gain-of-function approaches, as well as a pharmacological SIRT1 activation by SRT1720. We found that CS exposure increased protein oxidation and lipid peroxidation in lungs of wild-type (WT) mice, which was further augmented in SIRT1-deficient mice. Furthermore, both SIRT1 genetic overexpression and SRT1720 treatment significantly decreased oxidative stress induced by CS exposure. FOXO3 deletion augmented lipid peroxidation products but reduced antioxidants in response to CS exposure, which was not affected by SRT1720. Interestingly, SRT1720 treatment exhibited a similar effect on lipid peroxidation and antioxidants (i.e., manganese superoxide dismutase, heme oxygenase-1, and NADPH quinone oxidoreductase-1) in WT and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-deficient mice in response to CS exposure. This indicates that SIRT1 protects against CS-induced oxidative stress, which is mediated by FOXO3, but is independent of Nrf2. Overall, these findings reveal a novel function of SIRT1, which is to reduce CS-induced oxidative stress, and this may contribute to its protective effects against lung inflammation and subsequent development of COPD.

Description: Question What are the relative efficacy and safety of warfarin and aspirin in patients with heart failure who are in sinus rhythm? Methods Design Randomized controlled trial (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF] trial). ClinicalTrials.gov NCT00041938. Allocation {Concealed}*.† Blinding Blinded† (patients, clinicians, {data collectors, safety committee}*, and outcome assessors). Follow-up period ≤ 6 years (mean 3.5 y). Setting 168 centers in the USA, Canada, Argentina, and Europe. Patients 2305 adults ≥ 18 years of age (mean age 61 y, 80% men) who had a left ventricular ejection fraction (LVEF) ≤ 35% and normal sinus rhythm, and planned treatment with a β-blocker, angiotensin-converting enzyme inhibitor, or hydralazine and nitrates. Exclusion criteria included modified Rankin score 〉 4, medical conditions with high risk for cardiac embolism, clear indication for warfarin or aspirin, or contraindication to warfarin. Patients in New York Heart Association class I were eligible but could not comprise 〉 20% of randomized patients. Intervention Active warfarin (with target international normalized ratio 2.0 to 3.5) plus aspirin placebo ( n = 1142), or aspirin, 325 mg/d, plus warfarin placebo ( n = 1163). Outcomes Primary composite endpoint of ischemic stroke, intracerebral hemorrhage (ICH), or death. Secondary outcome was a composite of ischemic stroke, ICH, death, myocardial infarction, or hospitalization for heart failure. The safety outcome was a composite of ischemic stroke, ICH, death, or intracranial hemorrhage. The trial had 69% power to detect a relative hazard reduction of 17.8% in the primary outcome and 83% power for the secondary outcome. Patient follow-up {93%}* (96% for vital status; intention-to-treat analysis). Main results Enrolment was stopped early because of slow recruitment. Groups did not differ for the primary composite outcome or any of its components except for ischemic stroke (Table). Groups also did not differ for the secondary or safety composite endpoints (Table). Conclusion In patients with heart failure who are in sinus rhythm, warfarin and aspirin did not differ for a composite of death or ischemic or hemorrhage outcomes.Warfarin vs aspirin in patients with heart failure who are in sinus rhythm‡OutcomesEvents / 100 patient-yAt a mean 3.5 yWarfarinAspirinRRR (95% CI)NNT (CI)Primary composite§7.57.9{4% (−10 to 16)}||Not significantSafety composite¶7.68.0{3% (−11 to 15)}||Not significantRRI (CI)NNH (CI)Secondary composite**12.712.2{5% (−6 to 16)}||Not significant‡Abbreviations defined in Glossary.§Ischemic stroke {0.7 vs 1.4, RRR 46%, 95% CI 16 to 65}||, intracerebral hemorrhage {0.12 vs 0.05, RRI 155%, CI −51 to 1210}||, or death {6.6 vs 6.5, RRI 4%, CI −11 to 20}||.||Estimates provided by author.¶Ischemic stroke, intracerebral hemorrhage, death, or intracranial hemorrhage.**Ischemic stroke, intracerebral hemorrhage, death, myocardial infarction, or hospitalization for heart failure.