Abstract 19029: The Sirt1 Activator, SRT1720, Attenuates Cardiac Hypertrophy and Fibrosis in a Rodent Pressure Overload Model
Background: Transforming growth factor β1 (TGFβ1) is a prosclerotic cytokine involved in cardiac remodeling leading to heart failure (CHF). In order to precisely regulate TGFβ1 signaling, acetylation/de-acetylation of lysine19 within the MH1 domain of Smad2 has been shown to alter DNA binding and transcriptional activity. Recently the lysine de-acetylase Sirt1 has been shown to have a cardioprotective effect, however both Sirt1 expression and activity are reduced in CHF. We hypothesized that pharmacological activation of Sirt1 using SRT1720 would induce cardioprotection in a transverse aortic constriction (TAC) model through modulation of TGF-ß/Smad signaling.
Methods: Wildtype C57BL/6 mice were randomized to receive TAC or sham surgery at 8 weeks of age; each group was subsequently randomized to receive SRT1720 (100mg/kg/day) or placebo, administered once daily via oral gavage. Six weeks following TAC, cardiac function was assessed followed by left ventricular (LV) tissue collection for analysis.
Results: Animals randomized to TAC demonstrated reduced systolic function, LV hypertrophy and increased fibrosis (all p<0.05 compared with sham). Despite no difference in systolic pressure when compared with TAC + placebo, animals receiving TAC + SRT1720 demonstrated improved LVEF, reduced LV mass and reduced LV fibrosis (all p<0.05). Furthermore, assessment of the fetal gene program in TAC mice demonstrated increased expression of ß-MHC, α-SKA and ANP (all p<0.05 c/w sham) all of which were normalized by SRT1720 treatment (all p<0.05). Finally, TAC mice demonstrated increased phospho-Smad2 expression compared to sham, which was normalized by treatment with SRT1720 (p<0.05).
Conclusion: Treatment of mice with SRT1720 improves cardiac function and reduces cardiac fibrosis and hypertrophy following TAC. Given that Sirt1 expression and activity are reduced in CHF, enhancing Sirt1 activity may represent a novel intervention to reduce TGF-ß mediated fibrosis.
Author Disclosures: C.M. Ford: None. R.A. Civitarese: None. A. Bugyei-Twum: None. M. Mitchell: None. J. Desjardins: None. K. Thai: None. A. Abadeh: None. Y. Zhang: None. J. Switzer: None. A. Advani: None. R.E. Gilbert: None. K.A. Connelly: None.
- © 2014 by American Heart Association, Inc.