Geriatric Research Education and Clinical Center (GRECC), VA Maryland Health Care Center, Baltimore VA Medical Center, Baltimore, MD, USA.
Research Service, Baltimore VA Medical Center, Baltimore, MD, 21201, USA.
Curr Rheumatol Rep. 2018 Mar 17;20(4):16. doi: 10.1007/s11926-018-0724-6.
Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms.
Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.
衰老相关分子机制的过早激活，正成为包括硬皮病在内的许多疾病的一个重要致病因素。在衰老过程的中央调控因子中，有一组组蛋白去乙酰化酶被称为沉默调节蛋白（SIRTs）。最近的研究结果表明，这些分子是硬皮病皮肤和肺纤维化的病理生理参与者。本文旨在从与衰老相关的分子机制的角度，综述 SIRTs 在硬皮病中作用的最新研究。
尽管在这个快速发展的领域存在一定程度的争议，但大多数数据表明，与健康对照组和硬皮病动物模型相比，硬皮病患者组织中的 SIRT 水平降低。分子研究揭示了几种 SIRT 水平下降导致纤维化的机制，其中最受关注的是 TGF-β 信号通路的调节。在细胞培养和动物模型中激活 SIRTs 可产生抗纤维化作用。SIRT 水平和活性的下降，正成为硬皮病的病理生理致病因素。恢复 SIRTs 可能对硬皮病患者具有治疗作用。
