Downregulation of Sirt1 as aging change in advanced heart failure

Background: in congestive heart failure the balance between cell death and cell survival in cardiomyocytes is compromised. sirtuin 1 (sirt1) activates cell survival machinery and has been shown to be protective against ischemia/reperfusion injury in murine heart. the role of sirt1 in heart failure,especially in human hearts is not clear. results: the expression of sirt1 and other (associated) downstream molecules in human cardiomyocytes from patients with advanced heart failure was examined. sirt1 was down-regulated (54.92% ± 7.80% in advanced heart failure samples compared with healthy control cardiomyocytes). the modulation of molecules involved in cardiomyocyte survival and death in advanced heart failure were also examined. the expression of mn-superoxide dismutase and thioredoxin1,as well as an antiapoptotic molecule,bcl-xl,were all significantly reduced in advanced heart failure cardiomyoctes (0.71 ± 0.02-fold,0.61 ± 0.05-fold,and 0.53 ± 0.08-fold vs. control,respectively); whereas the expression of proapoptotic molecule bax was significantly increased (1.62 ± 0.18-fold vs. control). increased tunel-positive number of cardiomyocytes and oxidative stress,confirmed by 8-hydorxydeoxyguanosine staining,were associated with advanced heart failure. the ampk-nampt-sirt1 axis also showed inhibition in advanced heart failure in addition to severely impaired ampk activation. increased p53 (acetyl form) and decreased foxo1 translocation in the nucleus may be the mechanism of down-regulation of antioxidants and up-regulation of proapoptotic molecules due to low expression of sirt1. conclusion: in advanced heart failure,low sirt1 expression,like aging change may be a significant contributing factor in the downregulation of antioxidants and upregulation of proapoptotic molecules through the p53,foxo1,and oxidative stress pathways. © 2014 lu et al.; licensee biomed central ltd.