Activation and overexpression of Sirt1 attenuates lung fibrosis via P300

Zeng, Zhilin; Cheng, Sheng; Chen, Huilong; Li, Qinghai; Hu, Yinan; Wang, Qi; Zhu, Xianying; Wang, Jun

doi:10.1016/j.bbrc.2017.03.155

Cited by 64 publications

(53 citation statements)

References 40 publications

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“…Contradicting these findings, increased SIRT1 levels were found in SSc skin fibroblasts [102] and IPF lung tissues [98], as well as in bleomycin-treated mice [98, 102]. Another report showed increased SIRT6 expression in epithelial cells lining dilated cysts in patients with IPF, but not in normal lung, and upregulation of SIRT6 by TGF-β in primary human bronchial epithelial cells [118].…”

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

“…Wei et al found that SIRT1 disrupted Smad-dependent TGF-β signaling without affecting phosphorylation or nuclear translocation of Smad2, but suppressed p300, a known critical downstream component of the Smad pathway [100]. Zeng et al observed a similar potential role for p300 in mediating the effects of SIRT1 on fibrosis in a transformed fibroblast cell line [98]. Bai et al demonstrated increased fibrosis and Smad2 phosphorylation after SIRT1 shRNA intradermal injections in a mouse cutaneous wound model, implicating the TGF-β/Smad pathway in the regulation of scar formation by SIRT1 [103].…”

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

“…Important for the development of future therapies, SIRT1 activation with resveratrol suppresses collagen levels in cultured SSc skin fibroblasts [100, 102] and attenuates skin [102] and lung [98, 99] fibrosis and inflammation [99] in the bleomycin mouse model. Resveratrol treatment in mice prior to bleomycin had a more substantial effect than simultaneous or delayed treatment on reducing inflammatory responses and dermal thickness, suggesting that SIRT1 may play a preventative therapeutic role in early SSc [102].…”

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

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Sirtuins and Accelerated Aging in Scleroderma

Wyman

Atamas

2018

Curr Rheumatol Rep

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Purpose of Review 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. Recent Findings 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. Summary Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

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Section: Sirtuins and Sclerodermamentioning

confidence: 99%

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

Section: Sirtuins and Sclerodermamentioning

confidence: 99%

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Sirtuins and Accelerated Aging in Scleroderma

Wyman

Atamas

2018

Curr Rheumatol Rep

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“…Sirtuin-1 knockout in mice enhances lung fibrosis, and sirtuin-1 inhibits TGF-β fibroblast activation. Paradoxically sirtuin-1 is increased in the lungs of IPF patients, perhaps as a compensatory mechanism(66).Key role of microRNAMicroRNAs (miRNA) are small non-coding single-stranded RNAs (18-22 nucleotides) that regulate post-transcriptional gene expression through inducing degradation of mRNA or inhibiting translation by binding to complimentary sequences on the 3'-untranslated regulatory region of mRNAs.…”

mentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

341

264

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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“…Evidence has confirmed Sirt1 as a prime controller of pulmonary fibrosis, which depicts that the functioning and the overexpression of Sirt1 can contribute toward developing it as a therapeutic approach for IPF. 55 The study also explained the mechanism of Sirt1 via involvement of p300. Sirt1 is a major positive mediator of EMT induced via TGF-β, and excessive activity of Sirt1 can reverse the effect of EMT in lung cancer.…”

mentioning

confidence: 88%

Targeting anti‐aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis

Shaikh

Prabhu

Bhandary

2018

J of Cellular Biochemistry

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Idiopathic pulmonary fibrosis (IPF) is a severe, incurable, age‐associated respiratory disorder that has gained significance because of its unknown etiology and lack of therapeutic approaches. IPF causes maximum damage to the alveolar epithelial cells, thereby leading to lung remodeling and initiating epithelial to mesenchymal transition (EMT). The actual molecular mechanisms underlying IPF still remain unclear, and knowledge about these mechanisms would be helpful in its diagnosis. Sirtuins (Sirt) are class of NAD+‐dependent proteins, widely known to exert positive and protective effects on age‐related diseases such as diabetes, cancer, and so on, and are also involved in regulating IPF. The sirtuin family comprises of seven members (Sirt1 to Sirt7), out of which Sirt1, Sirt3, Sirt6, and Sirt7 exert positive effects on IPF. Sirt1 is associated with aging and inhibits cellular senescence and fibrosis. Sirt1 is well recognized in controlling pulmonary fibrosis and is also considered as a prime positive mediator of EMT. The expressions of Sirt3 protein tend to decline in IPF patients; hence it is known as an anti‐fibrotic protein. Sirt6 indeed has been proven to reduce EMT during IPF. Decreased levels of Sirt7 during IPF regulate lung fibroblasts. Hence, active levels of Sirt1, Sirt3, Sirt6, and Sirt7 can be attractive target models to elucidate a novel potential therapeutic approach for IPF. In this prospect, we have discussed the role of Sirtuins in pulmonary fibrosis by exploring the recent research evidence that highlight the role of sirtuins and also describes their protective effects.

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Activation and overexpression of Sirt1 attenuates lung fibrosis via P300

Cited by 64 publications

References 40 publications

Sirtuins and Accelerated Aging in Scleroderma

Sirtuins and Accelerated Aging in Scleroderma

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Targeting anti‐aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis

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