Session Type: Abstract Submissions (ACR)
Fibrosis in scleroderma is associated with increased collagen synthesis driven by TGF-β and associated epigenetic modifications. The Class III histone deacetylase SIRT1 has anticancer and anti-inflammatory properties in vitro and in vivo, and its expression and activation are induced by the natural phytoalexin resveratrol. We investigated SIRT1 function and regulation by resveratrol during fibrogenesis.
Methods: SIRT1 expression in scleroderma skin biopsies was analyzed in published microarray dataset. The effects of resveratrol on fibrotic responses were evaluated by real-time qPCR, Western analysis, immunefluorescence, transient transfection, collagen gel contraction and cell migration assays. SIRT1 modulation of TGF-β signaling was examined using the pharmacological SIRT1 inhibitors splitomicin and nicotinamide.
Results: Analysis of published microarray datasets revealed significant reduction of SIRT1 mRNA levels in skin biopsies from patients with diffuse cutaneous scleroderma n= 11, p<0.001). Resveratrol induced the activity of SIRT1 in explanted normal skin fibroblasts. Moreover, resveratrol blocked the stimulation of collagen gel contraction and cell migration induced by TGF-ß, and abrogated TGF-ß–induced collagen and α-smooth muscle actin expression, and Smad2/3-dependent transcriptional activity, in a dose-dependent manner. Ectopic SIRT1 by itself was sufficient to abrogate TGF-ß stimulated collagen expression, whereas pharmacological inhibition of SIRT prevented the anti-fibrotic activities of resveratrol.
Conclusion: Resveratrol abrogates canonical TGF-β signaling and suppresses fibrotic responses via the histone deacetylase and essential metabolic regulator SIRT1. Reduction of SIRT1 in scleroderma skin biopsies suggests its role in regulating fibrogenesis. Accordingly, we propose that SIRT1 is a novel target for anti-fibrotic therapy, and pharmacological enhancement of the SIRT1 expression or activity might have a therapeutic potential in scleroderma.
R. G. Marangoni,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-histone-deacetylase-sirt1-is-anti-fibrotic-and-mediates-resveratrol-effects/