期刊
CARDIOVASCULAR RESEARCH
卷 114, 期 12, 页码 1629-1641出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvy131
关键词
Heart failure; Fibrosis; Hypertrophy; TGF-beta signalling; Sirtuin 1
资金
- Heart and Stroke Foundation of Canada [NA6201]
- Canadian Institutes of Health Research
- Ministry of Ontario
- Canadian Institutes of Health Research Operating Grant [FRN119368]
- Canada Research Chairs
Aims Transforming growth factor beta 1 (TGF-beta 1) 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-beta 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-beta 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.
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