Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Recent evidences suggest that cytosolic and mitochondrial reactive oxygen species (ROS), play pivotal roles in modulating TGF-β-induced profibrotic responses and are implicated in pathogenesis of systemic sclerosis (SSc). The NAD+dependent deacetylase SIRT3 is a key regulator of mitochondrial ROS production. Honokiol activates cellular expression and activity of SIRT3. Here we investigated the anti-fibrotic potential of Honokiol and its synthetic analogues.
Methods: The expression of SIRT3 in fibroblasts was inquired in publicly-available microarray datasets and validated by real-time qPCR and Western analysis. The effects of SIRT3 activators on TGF-b-induced profibrotic responses were examined in neonatal foreskin fibroblasts, adult healthy and SSc dermal fibroblasts and normal human lung fibroblasts.
Results: Analysis of published microarray datasets revealed that TGF-β significantly suppresses SIRT3 mRNA expression in both healthy and SSc dermal fibroblasts. These results were validated by qPCR and Western analysis. Honokiol and its analogues stimulated SIRT3 expression and activation and abrogated TGF-b-induced collagen, a-smooth muscle actin and fibronectin EDA expression in neonatal foreskin fibroblasts and adult normal human lung fibroblasts. These results were confirmed by real-time qPCR, Western analysis and immunofluorescence. Moreover, ectopic expression of SIRT3 in normal fibroblasts dose-dependently abrogated TGF-β-induced collagen synthesis and myofibroblast differentiation. The inhibitory effects of honokiol analogues were diminished in SIRT3-null mouse embryonic fibroblasts.
Conclusion: Our results provide evidence that mitochondrial ROS play a role in fibroblast activation, and SIRT3 is a novel target for anti-fibrotic therapy. Pharmacological modulation of the SIRT3 expression or activity might have a therapeutic potential in SSc.
To cite this abstract in AMA style:Akamata K, Bhattacharyya M, Gupta M, Arbiser J, Kamp D, Wei J, Varga J. Pharmacologic Targeting of Mitochondrial Dysfunction in Systemic Sclerosis: Enhanced SIRT3 Signaling [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/pharmacologic-targeting-of-mitochondrial-dysfunction-in-systemic-sclerosis-enhanced-sirt3-signaling/. Accessed March 3, 2021.
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