The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling

Borkham-Kamphorst, Erawan; Schaffrath, C; Leur, Eddy Van de; Haas, Ute; Tihaa, Lidia; Meurer, Steffen K.; Nevzorova, Yulia A.; Liedtke, Christian; Weiskirchen, Ralf

doi:10.1016/j.bbamcr.2014.01.023

Cited by 91 publications

(79 citation statements)

References 38 publications

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“…CCN1, a matricellular protein, is highly expressed in injury repair and mediates varied and divergent cellular responses in cell-type and context-dependent manner (40). Recent reports suggest that CCN1 mediates profibrotic responses in the kidney (13,14), whereas it ameliorates skin (10) and liver fibrosis (11,12). Studies of the role of CCN1 in the lung are limited, although overexpression of CCN1 mediates neutrophilic alveolitis and acute lung injury in mice (15).…”

Section: Discussionmentioning

confidence: 99%

“…However, our results clearly demonstrate that IPF lung fibroblasts are dependent on endogenous CCN1 for robust activation of a profibrotic gene expression profile. Most of the antifibrotic effects of CCN1 reported in the literature involve young animals and nonsenescent fibroblasts (10)(11)(12)41). It would be interesting to test the effects of CCN1 abrogation/ silencing in aging models of injury fibrosis that may not be as dependent on proliferation as much as senescence to promote fibrotic remodeling (23).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that CCN1 may be beneficial in normal wound healing and tissue repair in contexts of resolving fibrosis but contribute to fibrosis in models of progressive fibrosis. Although the bleomycin model of lung fibrosis is known to be a slowly resolving model, we attempted to test the influence of targeting CCN1 by administering siRNA during the active fibrotic phase (d [8][9][10][11][12][13][14][15][16][17][18][19][20]. Future studies should address the effects of CCN1 in preclinical animal models of progressive fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…CCN1 has been shown to facilitate normal wound healing by inducing senescence of fibroblasts and limiting fibrosis (10). Additionally, exogenous CCN1 or genetic overexpression resulted in regression of established fibrosis in the liver (11,12). However, in some contexts, CCN1 appears to mediate proinflammatory and profibrotic effects, for example, following ischemic kidney injury (13) or unilateral ureteral obstruction (14).…”

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confidence: 99%

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The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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“…The inhibition of TSP1 expression at 1000 lM DETA/NO coincided with increased phosphorylation of p53 at Ser 15 and increased expression of MAP kinase phosphatase-1 (MKP1/DUSP1). Oxidative stress induces MKP1/DUSP1 expression in a p53-dependent manner (146), and both alterations are likely mediated by reactive nitrogen species (RNS) rather than directly by NO (272).…”

Section: E No Regulation Of Tsp1 Expressionmentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

Tsou

Khanna

Sawalha

2019

Arthritis & Rheumatology

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Objective We previously identified CYR61 as a histone deacetylase 5 (HDAC‐5)–repressed gene in systemic sclerosis (SSc; scleroderma) endothelial cells (ECs). When overexpressed, cysteine‐rich angiogenic inducer 61 (CYR‐61) promoted angiogenesis in SSc ECs. This study was undertaken to examine the role of CYR‐61 in fibrosis and determine the mechanisms involved in CYR‐61–mediated angiogenesis in SSc. Methods Dermal ECs and fibroblasts were isolated from biopsy specimens from healthy subjects and patients with SSc. CYR‐61 level was determined by quantitative polymerase chain reaction, Western blotting, and enzyme‐linked immunosorbent assay. CYR‐61 was overexpressed using a CYR61 vector or knocked down using small interfering RNA, and functional and mechanistic studies were then conducted in fibroblasts and ECs. Results Lower CYR61 messenger RNA levels were observed in dermal fibroblasts and ECs from SSc patients than in those from healthy controls. In SSc fibroblasts, overexpression of CYR‐61 led to significant reduction in the expression of profibrotic genes, including COL1A1 (P = 0.002) and ACTA2 (P = 0.04), and an increase in the expression of matrix‐degrading genes, including MMP1 (P = 0.002) and MMP3 (P =0.004), and proangiogenic VEGF (P = 0.03). The antifibrotic effect of CYR‐61 was further demonstrated by delay in wound healing, inhibition of gel contraction, inactivation of the transforming growth factor β pathway, and early superoxide production associated with senescence in SSc fibroblasts. In SSc ECs, overexpression of CYR‐61 led to increased production of vascular endothelial cell growth factor. The proangiogenic effects of CYR‐61 were mediated by signaling through αvβ3 receptors and downstream activation of AMP‐activated protein kinase, AKT, and the endothelial cell nitric oxide synthase/nitric oxide pathway system. Conclusion CYR‐61, which is epigenetically regulated by HDAC‐5, is a potent antifibrotic and proangiogenic mediator in SSc. Therapeutic intervention to promote CYR‐61 activity or increase CYR‐61 levels might be of benefit in SSc.

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The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling

Abstract: In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.

Cited by 91 publications

References 38 publications

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

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