&lt;p&gt;Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway&lt;/p&gt;

Zhang, Yan; Yuan, Dong; Xiong, Zhenyu; Zhu, Zhiguo; Gao, Fanya; Wang, Tingting; Man, Wanrong; Sun, Dong; Lin, Jie; Li, Tongbin; Li, Congye; Zhao, Zhiling; Shen, Min; Sun, Dongdong; Yang, Fan

doi:10.2147/dmso.s287287

Cited by 20 publications

(11 citation statements)

References 30 publications

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“…Moreover, SIRT6 de ciency induced aging-dependent multiorgan brosis in SIRT6 -/mice. Cardiac microvascular endothelial cells (CMECs)-speci c SIRT6 knockout appeared to worsen perivascular brosis and diabetic cardiomyopathy (DCM) in Type 2 diabetes mellitus (T2DM) [31]. Our results found that SIRT6 expression was up-regulated in IPF myo broblasts and MRC5 in the time and dose-dependent of TGF-β1 in vitro (Supplementary Fig2-3).…”

Section: Discussionmentioning

confidence: 69%

Activated mTORC1-SIRT6 Mediates Myofibroblast Differentiation and Idiopathic Pulmonary Fibrosis

Zhang¹,

Hu²,

Huang³

et al. 2021

Preprint

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BackgroundIdiopathic pulmonary fibrosis (IPF) is characterised by accumulation of myofibroblasts and deposition of extracellular matrix proteins. Fibroblast-to-myofibroblast transdifferentiation and myofibroblast hyperproliferation plays a major role in pulmonary fibrosis. Moreover, mTOR signaling pathway and SIRT6 play a critical role in pulmonary fibrosis. However, the mechanisms whether SIRT6 affect the myofibroblasts differentiation during IPF remain unclear.MethodWe investigated myofibroblast differentiation using a bleomycin-induced mouse pulmonary fibrosis model and TGF-b1 induced human fetal lung fibroblasts (MRC5) in vitro. We used both SIRT6 siRNA and rapamycin to study the role of SIRT6 and mTOR signaling pathway in the normal human lung fibroblasts and the myofibroblasts from human IPF lungs.ResultsOur data show that high level of SIRT6 was detected in IPF samples, and SIRT6 was signiﬁcantly upregulated by TGF-β1 in a time and concentration-dependent manner. SIRT6 expression and activation of mTORC1 signalling pathway were upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. Furthermore, rapamycin treatment inhibited mTORC1 pathway activity and SIRT6 protein expression. SIRT6 SiRNA failed to mediate the activity of mTORC1 pathway and autophagy induction. However, SIRT6 knockdown could promote TGF-b1 induced pro-fibrotic cytokines.ConclusionActivated mTORC1 signalling pathway regulated SIRT6 overexpression. Deficiency of SIRT6 mediated myofibroblasts differentiation through induced pro-fibrotic cytokines production in the present of TGF-β1. The study indicated that manipulations of SIRT6 expression may provide a new therapeutic strategy to prevent and reverse the progression of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 69%

Activated mTORC1-SIRT6 Mediates Myofibroblast Differentiation and Idiopathic Pulmonary Fibrosis

Zhang¹,

Hu²,

Huang³

et al. 2021

Preprint

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“…The EndMT process was observed not only during physiological development [24,46] and wound healing [47], but also during pathological processes, characterized by fibrosis, vascular injury and inflammation [24–28]. The use of lineage tracing models, assessing the EndMT in vivo , confirmed the EC lineage conversion [48].…”

Section: The Endmt Processmentioning

confidence: 99%

“…With regard to ECs, several reports [4,16,17] have confirmed the ability of these cells to transdifferentiate towards myofibroblasts through the endothelial‐to‐mesenchymal transition (EndMT), which is a non‐malignant phenomenon of cellular transdifferentiation by which ECs undergo a phonotypical differentiation, losing vascular ECs markers and gaining mesenchymal cell markers [2,18–22]. EndMT was first reported in studies on the physiological development of the heart [18,23] but, to date, this process is considered as a possible pathogenetic mechanism for different conditions, including cardiac fibrosis, kidney fibrosis, diabetic nephropathy, pulmonary hypertension and SSc [24–29]. Understanding the mechanism and functions of the EndMT process is pivotal to individuate early pathogenetic events and possibly new therapeutic targets for SSc in a very early phase, before the fibrotic process, which may be considered an end‐stage condition [10,30,31].…”

Section: Introductionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition in systemic sclerosis

Benedetto

Ruscitti

Berardicurti

et al. 2021

Clinical and Experimental Immunology

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Summary Systemic sclerosis (SSc) is an autoimmune disease characterized by significant vascular alterations and multi‐organ fibrosis. Microvascular alterations are the first event of SSc and injured endothelial cells (ECs) may transdifferentiate towards myofibroblasts, the cells responsible for fibrosis and collagen deposition. This process is identified as endothelial‐to‐mesenchymal transition (EndMT), and understanding of its development is pivotal to identify early pathogenetic events and new therapeutic targets for SSc. In this review, we have highlighted the molecular mechanisms of EndMT and summarize the evidence of the role played by EndMT during the development of progressive fibrosis in SSc, also exploring the possible therapeutic role of its inhibition.

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“…54 Similar results were obtained in a study on endothelium-specific Sirt6-KO mice and cardiac microvascular endothelial cells (CMECs). 52 Zhang and collaborators demonstrated that the absence of Sirt6 exacerbates the fibrogenic phenotype both in vivo and in vitro. In particular, Sirt6 repression favoured the EndMT process probably through the modulation of the Notch1 pathway.…”

Section: Sirt6 and Fibrosismentioning

confidence: 99%

“…In particular, Sirt6 repression favoured the EndMT process probably through the modulation of the Notch1 pathway. 52 Interestingly, the abolition of Sirt6 expression in proximal tubule (PT) cells from streptozotocin-treated diabetic mice, led to an up-regulation of the profibrotic gene tissue inhibitor of metalloproteinase 1 (TIMP1), collagen deposition and tubular basement membrane thickening, thus leading to a worse fibrotic phenotype in the kidney. 55 Similar results have been obtained in another transgenic mouse with PT-specific knockout of the nicotinamide phosphoribosyltransferase (NAMPT) gene, which drives the synthesis of nicotinamide mononucleotide (the NAD+ precursor).…”

Section: Sirt6 and Fibrosismentioning

confidence: 99%

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

Zullo

Mancini

Schleip

et al. 2021

Wound Repair Regeneration

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Fibrotic diseases are still a serious concern for public health, due to their high prevalence, complex etiology and lack of successful treatments. Fibrosis consists of excessive accumulation of extracellular matrix components. As a result, the structure and function of tissues are impaired, thus potentially leading to organ failure and death in several chronic diseases. Myofibroblasts represent the principal cellular mediators of fibrosis, due to their extracellular matrix producing activity, and originate from different types of precursor cells, such as mesenchymal cells, epithelial cells and fibroblasts. Profibrotic activation of myofibroblasts can be triggered by a variety of mechanisms, including the transforming growth factor-β signalling pathway, which is a major factor driving fibrosis. Interestingly, preclinical and clinical studies showed that fibrotic degeneration can stop and even reverse by using specific antifibrotic treatments. Increasing scientific evidence is being accumulated about the role of sirtuins in modulating the molecular pathways responsible for the onset and development of fibrotic diseases. Sirtuins are NAD +dependent protein deacetylases that play a crucial role in several molecular pathways within the cells, many of which at the crossroad between health and disease. In this context, we will report the current knowledge supporting the role of sirtuins in the balance between healthy and diseased myofibroblast activity. In particular, we will address the signalling pathways and the molecular targets that trigger the differentiation and profibrotic activation of myofibroblasts and can be modulated by sirtuins.

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<p>Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway</p>

Cited by 20 publications

References 30 publications

Activated mTORC1-SIRT6 Mediates Myofibroblast Differentiation and Idiopathic Pulmonary Fibrosis

Activated mTORC1-SIRT6 Mediates Myofibroblast Differentiation and Idiopathic Pulmonary Fibrosis

Endothelial-to-mesenchymal transition in systemic sclerosis

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

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