Sirtuin 1 activation attenuates cardiac fibrosis in a rodent pressure overload model by modifying Smad2/3 transactivation. Issue 12 (25th May 2018)

• Record Type: Journal Article
• Authors: Bugyei-Twum, Antoinette; Ford, Christopher; Civitarese, Robert; Seegobin, Jessica; Advani, Suzanne L; Desjardins, Jean-Francois; Kabir, Golam; Zhang, Yanling; Mitchell, Melissa; Switzer, Jennifer; Thai, Kerri; Shen, Vanessa; Abadeh, Armin; Singh, Krishna K; Billia, Filio; Advani, Andrew; Gilbert, Richard E; Connelly, Kim A
• Is Part Of: Cardiovascular research. Volume 114:Issue 12(2018)
• Page Start: 1629
• Page End: 1641
• Publication Date: 2018-05-25
• Subjects: Heart failure -- Fibrosis -- Hypertrophy -- TGF-β signalling -- Sirtuin 1; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvy131
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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.