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The European Respiratory Journal Mar 2016Activin-A is a pleiotropic cytokine that regulates allergic inflammation. Its role in the regulation of angiogenesis, a key feature of airways remodelling in asthma,...
Activin-A is a pleiotropic cytokine that regulates allergic inflammation. Its role in the regulation of angiogenesis, a key feature of airways remodelling in asthma, remains unexplored. Our objective was to investigate the expression of activin-A in asthma and its effects on angiogenesis in vitro.Expression of soluble/immunoreactive activin-A and its receptors was measured in serum, bronchoalveolar lavage fluid (BALF) and endobronchial biopsies from 16 healthy controls, 19 patients with mild/moderate asthma and 22 severely asthmatic patients. In vitro effects of activin-A on baseline and vascular endothelial growth factor (VEGF)-induced human endothelial cell angiogenesis, signalling and cytokine release were compared with BALF concentrations of these cytokines in vivo.Activin-A expression was significantly elevated in serum, BALF and bronchial tissue of the asthmatics, while expression of its protein receptors was reduced. In vitro, activin-A suppressed VEGF-induced endothelial cell proliferation and angiogenesis, inducing autocrine production of anti-angiogenic soluble VEGF receptor (R)1 and interleukin (IL)-18, while reducing production of pro-angiogenic VEGFR2 and IL-17. In parallel, BALF concentrations of soluble VEGFR1 and IL-18 were significantly reduced in severe asthmatics in vivo and inversely correlated with angiogenesis.Activin-A is overexpressed and has anti-angiogenic effects in vitro that are not propagated in vivo, where reduced basal expression of its receptors is observed particularly in severe asthma.
Topics: Activins; Adult; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cell Line; Cell Proliferation; Cytokines; Endothelial Cells; Female; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-17; Interleukin-18; Male; Middle Aged; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor; Severity of Illness Index; Vascular Endothelial Growth Factor A
PubMed: 26869672
DOI: 10.1183/13993003.00437-2015 -
Nucleic Acids Research Oct 2022Transforming growth factor β (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Nodal/Activin/TGF-β and BMP ligands are...
Transforming growth factor β (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Nodal/Activin/TGF-β and BMP ligands are both present in the intra- and extracellular milieu during early development, and cross-talk between these two branches of developmental signaling is currently the subject of intense research focus. Here, we show that the Nodal induced lncRNA-Smad7 regulates cell fate determination via repression of BMP signaling in mouse embryonic stem cells (mESCs). Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, lncRNA-Smad7 represses Bmp2 expression through binding with the Bmp2 promoter region via (CA)12-repeats that forms an R-loop. Importantly, Bmp2 knockdown rescues defects in cardiomyocyte differentiation induced by lncRNA-Smad7 knockdown. Hence, lncRNA-Smad7 antagonizes BMP signaling in mESCs, and similarly regulates cell fate determination between osteocyte and myocyte formation in C2C12 mouse myoblasts. Moreover, lncRNA-Smad7 associates with hnRNPK in mESCs and hnRNPK binds at the Bmp2 promoter, potentially contributing to Bmp2 expression repression. The antagonistic effects between Nodal/TGF-β and BMP signaling via lncRNA-Smad7 described in this work provides a framework for understanding cell fate determination in early development.
Topics: Activins; Animals; Cell Differentiation; Ligands; Mice; RNA, Long Noncoding; Smad7 Protein; Transforming Growth Factor beta
PubMed: 36134711
DOI: 10.1093/nar/gkac780 -
Cancer Research Jun 2006The transforming growth factor-beta superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell...
The transforming growth factor-beta superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2-induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained.
Topics: Activins; Animals; Apoptosis; Breast Neoplasms; Carcinoma, Renal Cell; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Follistatin; Humans; Kidney Neoplasms; Mice; Mice, Nude; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Transfection; Transplantation, Heterologous
PubMed: 16740706
DOI: 10.1158/0008-5472.CAN-05-3821 -
Diabetes & Vascular Disease Research Jul 2012Silent coronary artery disease is a frequent complication of type 2 diabetes (T2DM). Based on its multiple roles in inflammation, atherogenesis and glucose homeostasis,...
BACKGROUND
Silent coronary artery disease is a frequent complication of type 2 diabetes (T2DM). Based on its multiple roles in inflammation, atherogenesis and glucose homeostasis, we hypothesised that activin A could be related to coronary atherosclerosis in T2DM.
METHODS
Activin A and follistatin were measured in 102 patients with T2DM and 20 age- and sex-matched healthy controls. Coronary angiography was performed in a sub-population of patients and associations with activin A were examined using multiple linear regression.
RESULTS
Serum activin A and the activin A/follistatin ratio were increased in patients with T2DM and coronary artery disease (CAD) compared with healthy volunteers and the elevated activin A was associated with the severity of coronary atherosclerotic burden as determined by the proportion of ≥2 vessel disease (p = 0.035) after multivariable-adjusted trend analysis. No significant association between presence of CAD or extent score and activin A was observed.
CONCLUSION
In patients with T2DM, increased activin A may reflect chronic underlying pathophysiological processes involved in development of cardiovascular disease.
Topics: Activins; Adult; Aged; Case-Control Studies; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follistatin; Humans; Inflammation; Linear Models; Male; Middle Aged
PubMed: 22234949
DOI: 10.1177/1479164111431171 -
Frontiers in Endocrinology 2022Activin A, a TGFβ superfamily member, is important for normal testis development through its actions on Sertoli cell development. Our analyses of altered activin A...
Activin A, a TGFβ superfamily member, is important for normal testis development through its actions on Sertoli cell development. Our analyses of altered activin A mouse models indicated gonocyte abnormalities, implicating activin A as a key determinant of early germline formation. Whether it acts directly or indirectly on germ cells is not understood. In humans, the fetal testis may be exposed to abnormally elevated activin A levels during preeclampsia, maternal infections, or following ingestion of certain medications. We hypothesized that this may impact fetal testis development and ultimately affect adult fertility. Germ cells from two mouse models of altered activin bioactivity were analysed. RNA-Seq of gonocytes purified from E13.5 and E15.5 KO mice (activin A subunit knockout) identified 46 and 44 differentially expressed genes (DEGs) respectively, and 45 in the E13.5 KO (inhibin alpha subunit knockout; increased activin A) gonocytes. To discern direct effects of altered activin bioactivity on germline transcripts, isolated E13.5 gonocytes were cultured for 24h with activin A or with the activin/Nodal/TGFβ inhibitor, SB431542. Gonocytes responded directly to altered signalling, with activin A promoting a more differentiated transcript profile (increased differentiation markers and ; decreased early germ cell markers and ), while SB431542 had a reciprocal effect (decreased and ; increased ). To delineate direct and indirect effects of activin A exposure on gonocytes, whole testes were cultured 48h with activin A or SB431542 and collected for histological and transcript analyses, or EdU added at the end of culture to measure germ and Sertoli cell proliferation using flow cytometry. Activin increased, and SB431542 decreased, Sertoli cell proliferation. SB431542-exposure resulted in germ cells escaping mitotic arrest. Analysis of FACS-isolated gonocytes following whole testis culture showed SB431542 increased the early germ cell marker , however there was a general reduction in the impact of altered activin A bioavailability in the normal somatic cell environment. This multifaceted approach identifies a capacity for activin A to directly influence fetal germ cell development, highlighting the potential for altered activin A levels to increase the risk of testicular pathologies that arise from impaired germline maturation.
Topics: Activins; Animals; Argonaute Proteins; Germ Cells; Male; Mice; RNA-Binding Proteins; Testis; Transforming Growth Factor beta
PubMed: 35721752
DOI: 10.3389/fendo.2022.896747 -
Cancer Treatment and Research... 2022Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC)....
BACKGROUND
Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC). Resistance to platinum chemotherapy is common, and predictive biomarkers are needed to tailor treatment to patients likely to respond. In vitro evidence implicates the transforming growth factor-β (TGF-β) superfamily ligands activin-A and growth differentiation factor 11 (GDF-11) in innate platinum resistance. We performed a validation study to assess their utility as predictive biomarkers of platinum chemotherapy response in advanced NSCLC.
PATIENTS AND METHODS
Our study included 123 adult patients with advanced NSCLC without a driver mutation treated with platinum chemotherapy. 98 patients were from a retrospective cohort and 25 from a prospective cohort. We performed immunohistochemistry staining for Activin-A, GDF-11 and TGF-β on tumour samples for each patient and analysed IHC expression with objective radiological response and overall survival.
RESULTS
The overall median survival was 14.8 months. We performed statistical analysis around a cytoplasmic score of 8/18 for Activin-A and GDF-11 based on previously published work, and 110/30 for TGF-β based on a calculated cutpoint for significance. No survival difference was detected between these groups for Activin-A (p=0.35), GDF-11 (p=0.57) or TGF-β (p=0.34). There was no association between rates of progressive disease and high Activin-A expression (p=0.43), high GDF-11 expression (p=1.0) or high TGF-β expression p=0.89).
CONCLUSION
Within the confines of our study, Activin-A, GDF-11 and TGF-β expression was not a predictor of objective radiological response to chemotherapy or overall survival.
Topics: Activins; Adult; Biomarkers; Bone Morphogenetic Proteins; Carcinoma, Non-Small-Cell Lung; Growth Differentiation Factors; Humans; Lung Neoplasms; Organoplatinum Compounds; Platinum; Prospective Studies; Retrospective Studies; Transforming Growth Factor beta; Transforming Growth Factors
PubMed: 35597155
DOI: 10.1016/j.ctarc.2022.100576 -
Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling.Disease Models & Mechanisms May 2022In the heart, ageing is associated with DNA damage, oxidative stress, fibrosis and activation of the activin signalling pathway, leading to cardiac dysfunction. The...
In the heart, ageing is associated with DNA damage, oxidative stress, fibrosis and activation of the activin signalling pathway, leading to cardiac dysfunction. The cardiac effects of activin signalling blockade in progeria are unknown. This study investigated the cardiac effects of progeria induced by attenuated levels of Ercc1, which is required for DNA excision and repair, and the impact of activin signalling blockade using a soluble activin receptor type IIB (sActRIIB). DNA damage and oxidative stress were significantly increased in Ercc1Δ/- hearts, but were reduced by sActRIIB treatment. sActRIIB treatment improved cardiac systolic function and induced cardiomyocyte hypertrophy in Ercc1Δ/- hearts. RNA-sequencing analysis showed that in Ercc1Δ/- hearts, there was an increase in pro-oxidant and a decrease in antioxidant gene expression, whereas sActRIIB treatment reversed this effect. Ercc1Δ/- hearts also expressed higher levels of anti-hypertrophic genes and decreased levels of pro-hypertrophic ones, which were also reversed by sActRIIB treatment. These results show for the first time that inhibition of activin A receptor signalling attenuates cardiac dysfunction, pathological tissue remodelling and gene expression in Ercc1-deficient mice and presents a potentially novel therapeutic target for heart diseases.
Topics: Activins; Animals; Heart Diseases; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Progeria; Ventricular Remodeling
PubMed: 35380160
DOI: 10.1242/dmm.049424 -
Cellular and Molecular Gastroenterology... 2022Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine...
BACKGROUND & AIMS
Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development.
METHODS
We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed bromouridine sequencing analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1a; LSL-Kras; Trp53; Kdm6a, Ptf1a; Kdm6a, and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis.
RESULTS
Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata.
CONCLUSIONS
Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.
Topics: Activins; Animals; Cell Plasticity; Histone Demethylases; Humans; Mice; Pancreas; Pancreatic Neoplasms
PubMed: 34583087
DOI: 10.1016/j.jcmgh.2021.09.014 -
Lung Oct 2021Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown cause with a variable course. Acute exacerbations of IPF (AE-IPF) is...
PURPOSE
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown cause with a variable course. Acute exacerbations of IPF (AE-IPF) is sudden accelerations of the disease or a superimposed idiopathic acute injury significantly reducing lung function. To examine the serum concentrations of Progranulin (PGRN) and activin A in patients with AE-IPF in a pilot study.
METHODS
Twenty-one patients with AE-IPF were compared with 23 patients with stable IPF as a control group. Serum PGRN and activin A levels, arterial blood gas measurements, and lung function were determined in these two groups.
RESULTS
Peripheral blood PGRN and activin A levels in patients with AE-IPF were 83.7 + 10.0 and 14.2 ± 1.7 ng/ml (mean + SD), respectively; higher than those in the control group 61.0 + 5.8 and 5.8 + 1.0 (p < 0.001). PGRN and activin A levels were significantly negatively correlated with carbon monoxide diffusion capacity r = - 0.857 (p < 0.001) and r = - 0.757 (p < 0.001).
CONCLUSION
Progranulin (PGRN) and activin A may be involved in the pathogenesis of AE-IPF. They may be possible markers of disease activity in AE-IPF.
Topics: Activins; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Pilot Projects; Prognosis; Progranulins
PubMed: 34462814
DOI: 10.1007/s00408-021-00470-6 -
PloS One 2023Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.
METHODS
We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.
RESULTS
Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.
CONCLUSION
These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.
Topics: Male; Female; Humans; Aged; Sarcopenia; Myostatin; Activin Receptors; Cross-Sectional Studies; Body Composition; Activins; Muscle, Skeletal
PubMed: 37963137
DOI: 10.1371/journal.pone.0294330