Adenosine A2A receptors promote collagen production by a Fli1- and CTGF-mediated mechanism

Chan, Edwin S. L.; Liu, Hailing; Fernández, Patricia; Luna, Alex; Pérez-Aso, Miguel; Bujor, Andreea M.; Trojanowska, Maria; Cronstein, Bruce N.

doi:10.1186/ar4229

Cited by 39 publications

(42 citation statements)

References 43 publications

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“…Furthermore, ADORA2A stimulation in dermal fibroblasts induces an augment in the abundance of collagen 1 and 3 proteins, and its blockade prevents pharmacologically-induced dermal fibrosis [97]; it has been described that this effect is mediated by the cAMP accumulation elicited by ADORA2A activity and by a subsequent AKT activation, but it is independent of the TGF-β/SMAD pathway [132]. Downstream, ADORA2A stimulation regulates the activity of Fli-1 and CTGF transcription factors to modulate the expression level of collagen I gene [133].…”

Section: Purinergic Signaling Emt and Fibrosismentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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Section: Purinergic Signaling Emt and Fibrosismentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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“…A 2A R also promotes Col1 synthesis by a connective tissue growth factor (CTGF)-dependent mechanism, and this effect is not abrogated with AKT knockdown indicating that it is an independent pathway [39]. Constitutive expression of CTGF in fibroblasts is sufficient to cause accelerated diffuse tissue fibrosis in vivo [40].…”

Section: The Role Of Adenosine and Its Receptors In Granulation Tissumentioning

confidence: 99%

“…It has been shown to be an important regulator of collagen production in vivo by repressing collagen genes such as Col1A1, Col1A2, and Col3A1. Fli1 has also been shown to be significantly reduced in clinically involved skin of scleroderma patients [39]. A 2A R occupancy in dermal fibroblasts promotes reduced nuclear Fli1 mRNA and protein expression with correspondingly increased CTGF protein expression and secretion [39].…”

Section: The Role Of Adenosine and Its Receptors In Granulation Tissumentioning

confidence: 99%

“…Fli1 has also been shown to be significantly reduced in clinically involved skin of scleroderma patients [39]. A 2A R occupancy in dermal fibroblasts promotes reduced nuclear Fli1 mRNA and protein expression with correspondingly increased CTGF protein expression and secretion [39]. TGF-beta pathway activation has also been shown to acetylate Fli1 in dermal fibroblasts, which renders Fli1 less stable thereby promoting extracellular matrix production.…”

Section: The Role Of Adenosine and Its Receptors In Granulation Tissumentioning

confidence: 99%

“…TGF-beta pathway activation has also been shown to acetylate Fli1 in dermal fibroblasts, which renders Fli1 less stable thereby promoting extracellular matrix production. Fli1 thus serves as another potential link between these two important pro-fibrotic pathways [39].…”

Section: The Role Of Adenosine and Its Receptors In Granulation Tissumentioning

confidence: 99%

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Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

Shaikh

Cronstein

2016

Purinergic Signalling

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Collagen and matrix deposition by fibroblasts is an essential part of wound healing but also contributes to pathologic remodeling of organs leading to substantial morbidity and mortality. Adenosine, a small molecule generated extracellularly from adenine nucleotides as a result of direct stimulation, hypoxia, or injury, acts via a family of classical sevenpass G protein-coupled protein receptors, A 2A and A 2B , leading to generation of cAMP and activation of downstream targets such as PKA and Epac. These effectors, in turn, lead to fibroblast activation and collagen synthesis. The regulatory actions of these receptors likely involve multiple interconnected pathways, and one of the more interesting aspects of this regulation is opposing effects at different levels of cAMP generated. Additionally, adenosine signaling contributes to fibrosis in organ-specific ways and may have opposite effects in different organs. The development of drugs that selectively target these receptors and their signaling pathways will disrupt the pathogenesis of fibrosis and slow or arrest the progression of the important diseases they underlie.

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Fibrosis, Vascular Activation, and Immune Abnormalities Resembling Systemic Sclerosis in Bleomycin‐Treated Fli‐1–Haploinsufficient Mice

Taniguchi

Asano

Akamata

et al. 2015

Arthritis & Rheumatology

Self Cite

113

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Objective Fli-1, a potential predisposing factor for systemic sclerosis (SSc), is constitutively down-regulated in the lesional skin of patients with SSc by an epigenetic mechanism. To investigate the impact of Fli-1 deficiency on the induction of an SSc phenotype in various cell types, we generated bleomycin-induced skin fibrosis in Fli-1+/− mice and investigated the molecular mechanisms underlying its phenotypic alterations. Methods Messenger RNA (mRNA) levels and protein expression of target molecules were examined by quantitative reverse transcription–polymerase chain reaction and immunostaining. Transforming growth factor β (TGFβ) bioassay was used to evaluate the activation of latent TGFβ. The binding of Fli-1 to the target gene promoters was assessed with chromatin immunoprecipitation. Results Bleomycin induced more severe dermal fibrosis in Fli-1+/− mice than in wild-type mice. Fli-1 haploinsufficiency activated dermal fibroblasts via the up-regulation of αvβ3 and αvβ5 integrins and activation of latent TGFβ. Dermal fibrosis in Fli-1+/− mice was also attributable to endothelial-to-mesenchymal transition, which is directly induced by Fli-1 deficiency and amplified by bleomycin. Th2/Th17-skewed inflammation and increased infiltration of mast cells and macrophages were seen, partly due to the altered expression of cell adhesion molecules in endothelial cells as well as the induction of the skin chemokines. Fli-1+/− mouse macrophages preferentially differentiated into an M2 phenotype upon stimulation with interleukin-4 (IL-4) or IL-13. Conclusion Our findings provide strong evidence for the fundamental role of Fli-1 deficiency in inducing SSc-like phenotypic alterations in dermal fibroblasts, endothelial cells, and macrophages in a manner consistent with human disease.

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Adenosine A2A receptors promote collagen production by a Fli1- and CTGF-mediated mechanism

Cited by 39 publications

References 43 publications

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

Fibrosis, Vascular Activation, and Immune Abnormalities Resembling Systemic Sclerosis in Bleomycin‐Treated Fli‐1–Haploinsufficient Mice

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