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

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 cardioprotectiveeffect; however, SIRT1 expression and activity are paradoxically reduced in HF. Herein, we investigate whether pharmacological activation of SIRT1 would induce cardioprotectionin a pressure overloadmodel and assess the impact of SIRT1 activation on TGF-β signalling and the fibrotic response.Eight weeks old male C57BL/6 mice were randomized to undergo sham surgeryor transverse aortic constriction (TAC) to induce pressure overload. Post-surgery, animals were further randomized to receive SRT1720or vehicle treatment. Echocardiography, pressure-volume loops, and histological analysis revealed an impairment in cardiac function and deleterious left ventricular remodellingin TAC-operated animals that was improved with SRT1720treatment. Genetic ablation and cell culture studies using a Smad-binding response element revealed SIRT1 to be a specific target of SRT1720and identified Smad2/3 as a SIRT1 specific substrate.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 Smadactivity.