Sirtuin 1 activation attenuates cardiac fibrosis in a rodent pressure overload model by modifying Smad2/3 transactivation

Cardiovasc Res. 2018 Oct 1;114(12):1629-1641. doi: 10.1093/cvr/cvy131.


Aims: Transforming growth factor β1 (TGF-β1) is a prosclerotic cytokine involved in cardiac remodelling leading to heart failure (HF). Acetylation/de-acetylation of specific lysine residues in Smad2/3 has been shown to regulate TGF-β signalling by altering its transcriptional activity. Recently, the lysine de-acetylase sirtuin 1 (SIRT1) has been shown to have a cardioprotective effect; however, SIRT1 expression and activity are paradoxically reduced in HF. Herein, we investigate whether pharmacological activation of SIRT1 would induce cardioprotection in a pressure overload model and assess the impact of SIRT1 activation on TGF-β signalling and the fibrotic response.

Methods and results: Eight weeks old male C57BL/6 mice were randomized to undergo sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Post-surgery, animals were further randomized to receive SRT1720 or vehicle treatment. Echocardiography, pressure-volume loops, and histological analysis revealed an impairment in cardiac function and deleterious left ventricular remodelling in TAC-operated animals that was improved with SRT1720 treatment. Genetic ablation and cell culture studies using a Smad-binding response element revealed SIRT1 to be a specific target of SRT1720 and identified Smad2/3 as a SIRT1 specific substrate.

Conclusion: Overall, our data demonstrate that Smad2/3 is a specific SIRT1 target and suggests that pharmacological activation of SIRT1 may be a novel therapeutic strategy to prevent/reverse HF via modifying Smad activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Activators / pharmacology*
  • Fibrosis
  • Heart Failure / enzymology
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Histones / metabolism
  • Humans
  • Hypertrophy, Left Ventricular / enzymology
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Signal Transduction / drug effects
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Ventricular Function, Left / drug effects*
  • Ventricular Remodeling / drug effects*


  • Enzyme Activators
  • Heterocyclic Compounds, 4 or More Rings
  • Histones
  • SRT1720
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1