Browsing by Author "Brandan, Enrique"

Now showing 1 - 20 of 130
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    A Novel Modulatory Mechanism of Transforming Growth Factor-β Signaling through Decorin and LRP-1
    (2007) Cabello Verrugio, Claudio Alejandro; Brandan, Enrique
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    ACE2 is augmented in dystrophic skeletal muscle and plays a role in decreasing associated fibrosis
    (2014) Riquelme Illanes, Cecilia Angélica; Acuna, M.; Torrejon, J.; Rebolledo, D.; Cabrera, D.; Santos, R.; Brandan, Enrique
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    Activation of skeletal muscle FAPs by LPA requires the Hippo signaling via the FAK pathway
    (2023) Cruz-Soca, Meilyn; Faundez-Contreras, Jennifer; Cordova-Casanova, Adriana; Gallardo, Felipe S.; Bock-Pereda, Alexia; Chun, Jerold; Carlos Casar, Juan; Brandan, Enrique
    Lysophosphatidic acid (LPA) is a lysophospholipid that signals through six G-protein coupled receptors (LPARs), LPA1 to LPA6. LPA has been described as a potent modulator of fibrosis in different pathologies. In skeletal muscle, LPA increases fibrosis-related proteins and the number of fibro/adipogenic progenitors (FAPs). FAPs are the primary source of ECM-secreting myofibroblasts in acute and chronic damage. How-ever, the effect of LPA on FAPs activation in vitro has not been explored. This study aimed to investigate FAPs' response to LPA and the downstream signaling mediators involved. Here, we demonstrated that LPA mediates FAPs activation by increasing their proliferation, expression of myofibroblasts markers, and upregu-lation of fibrosis-related proteins. Pretreatment with the LPA1/LPA3 antagonist Ki16425 or genetic deletion of LPA1 attenuated the LPA-induced FAPs activation, resulting in decreased expression of cyclin e1, a-SMA, and fibronectin. We also evaluated the activation of the focal adhesion kinase (FAK) in response to LPA. Our results showed that LPA induces FAK phosphorylation in FAPs. Treatment with the P-FAK inhibitor PF-228 partially prevented the induction of cell responses involved in FAPs activation, suggesting that this pathway mediates LPA signaling. FAK activation controls downstream cell signaling within the cytoplasm, such as the Hippo pathway. LPA induced the dephosphorylation of the transcriptional coactivator YAP (Yes-associated protein) and promoted direct expression of target pathway genes such as Ctgf/Ccn2 and Ccn1. The blockage of YAP transcriptional activity with Super-TDU further confirmed the role of YAP in LPA-induced FAPs activa-tion. Finally, we demonstrated that FAK is required for LPA-dependent YAP dephosphorylation and the induc-tion of Hippo pathway target genes. In conclusion, LPA signals through LPA1 to regulate FAPs activation by activating FAK to control the Hippo pathway.(c) 2023 Elsevier B.V. All rights reserved.
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    Activation of the ATX/LPA/LPARs axis induces a fibrotic response in skeletal muscle
    (2022) Cordova-Casanova, Adriana; Cruz-Soca, Meilyn; Chun, Jerold; Carlos Casar, Juan; Brandan, Enrique
    Several common chronic diseases, muscular dystrophies (MDs), and aging lead to progressive fibrous connective tissue (fibrosis) accumulation in skeletal muscle. Cumulative past evidence points to the role of signaling lipids such as lysophosphatidic acid (LPA) and its receptors (LPARs) in different models of fibrosis. However, the potential contribution of these molecules to the fibrotic process in skeletal muscle has not been explored. Here, we show the expression of ATX/LPA/LPARs axis components in skeletal muscle, which suggests their potential relevance for the biology of this tissue. We investigated if the skeletal muscle responds to the stimulus of intramuscular (IM) LPA injections, finding an early induction of the pro-fibrotic factor connective tissue growth factor/Cellular Communication Network factor 2 (CCN2) and extracellular matrix (ECM) proteins. Also, we found that LPA induces an increase in the number of fibro/adipogenic progenitors (FAPs), which are the primary cellular source of myofibroblasts. These effects were for the most part prevented by the inhibitor Ki16425, which inhibits the LPA receptors LPA(1) and LPA(3), as well as in the LPA(1)-KO mice. We also evaluated the in vivo activation of extracellular signal-regulated kinases (ERK 1/2), AKT, c-Jun N-terminal kinase (JNK), and Yes-asocciated protein 1 (YAP) in response to LPA. Our results show that LPA induces ERK 1/2 phosphorylation in WT muscle, but not in LPA1-KO mice. Treatment with the ERK 1/2 inhibitor U0126 prevented the induction of fibronectin in response to LPA, suggesting that this pathway is involved in LPA-induced fibrosis. Altogether, these results demonstrate that ATX/LPA/LPARs constitute a pro-fibrotic axis and suggest a possible role in muscular diseases. (C) 2022 Elsevier B.V. All rights reserved.
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    Adenovirus-mediated hepatic syndecan-1 overexpression induces hepatocyte proliferation and hyperlipidaemia in mice
    (2007) Cortés, V.; Zanlungo Matsuhiro, Silvana; Brandan, Enrique; Rigotti Rivera, Attilio
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    ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers
    (2017) Gonzalez, David; Contreras Saavedra, Osvaldo Isaías; Brandan, Enrique; Rebolledo López, Daniela Victoria; Espinoza, Juan Pablo; Zundert, Brigitte van
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    Analysis of Pathological Activities of CCN2/CTGF in Muscle Dystrophy
    (2017) Acuña, Maria José; Brandan, Enrique
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    Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis
    (2017) Cabrera, Daniel; Wree, Alexander; Povero, Davide; Solís, Nancy; Hernández, Alejandra; Pizarro Rojas, Margarita Alicia; Moshage, Han; Torres Montes, Paula Javiera; Feldstein, Ariel E.; Cabello Verrugio, Claudio Alejandro; Brandan, Enrique; Barrera Martínez, Francisco Javier; Arab Verdugo, Juan Pablo; Arrese Jiménez, Marco
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    Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis
    (2014) Cabrera, D.; Gutiérrez, J.; Cabello Verrugio, Claudio Alejandro; Morales, M. G.; Mezzano, S.; Fadic Ruiz, Ricardo Julio Nicolás; Casar Leturia, Juan Carlos; Hancke, J. L.; Brandan, Enrique
    Background: Duchenne muscular dystrophy (DMD) is characterized by the absence of the cytoskeletal protein dystrophin, muscle wasting, increased transforming growth factor type beta (TGF-β) signaling, and fibrosis. At the present time, the only clinically validated treatments for DMD are glucocorticoids. These drugs prolong muscle strength and ambulation of patients for a short term only and have severe adverse effects. Andrographolide, a bicyclic diterpenoid lactone, has traditionally been used for the treatment of colds, fever, laryngitis, and other infections with no or minimal side effects. We determined whether andrographolide treatment of mdx mice, an animal model for DMD, affects muscle damage, physiology, fibrosis, and efficiency of cell therapy.Methods: mdx mice were treated with andrographolide for three months and skeletal muscle histology, creatine kinase activity, and permeability of muscle fibers were evaluated. Fibrosis and TGF-β signaling were evaluated by indirect immunofluorescence and Western blot analyses. Muscle strength was determined in isolated skeletal muscles and by a running test. Efficiency of cell therapy was determined by grafting isolated skeletal muscle satellite cells onto the tibialis anterior of mdx mice.Results: mdx mice treated with andrographolide exhibited less severe muscular dystrophy than untreated dystrophic mice. They performed better in an exercise endurance test and had improved muscle strength in isolated muscles, reduced skeletal muscle impairment, diminished fibrosis and a significant reduction in TGF-β signaling. Moreover, andrographolide treatment of mdx mice improved grafting efficiency upon intramuscular injection of dystrophin-positive satellite cells.Conclusions: These results suggest that andrographolide could be used to improve quality of life in individuals with DMD.
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    Angiotensin II receptor type 1 blockade decreases CTGF/CCN2-mediated damage and fibrosis in normal and dystrophic skeletal muscles
    (2012) Cabello Verrugio, Claudio Alejandro; Morales France, María Gabriela; Vio Lagos, Carlos P.; Brandan, Enrique
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    Angiotensin II-induced pro-fibrotic effects require p38MAPK activity and transforming growth factor beta 1 expression in skeletal muscle cells
    (2012) Morales France, María Gabriela; Brandan, Enrique; Cabello Verrugio, Claudio Alejandro
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    Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas
    (2016) Morales, M. G.; Abrigo, J.; Acuña M. J.; Santos, Ra.; Bader, M.; Brandan, Enrique; Simon, F.; Olguín Marín, Hugo César; Cabrera, D.; Cabello Verrugio, Claudio Alejandro
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    Angiotensin-(1-7) prevents lipopolysaccharide-induced autophagy via the mas receptor in skeletal muscle
    (2020) Rivera, J. C.; Abrigo, J.; Tacchi, F.; Simón, F.; Brandan, Enrique; Santos, R. A.; Bader, M.; Chiong, M.; Cabello Verrugio, Claudio Alejandro
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    Angiotensins as therapeutic targets beyond heart disease
    (2015) Passos Silva, Danielle Gomes; Brandan, Enrique; Souza Santos, Robson Augusto
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    Antisense Inhibition of Decorin Expression in Myoblasts Decreases Cell Responsiveness to Transforming Growth Factor B and Accelerates Skeletal Muscle Defferentiation
    (Elsevier Inc, 2001) Riquelme Illanes, Cecilia Angélica; Larraín Correa, Juan Agustín; Schönherr, Elke; Henríquez, Juan Pablo; Kresse, Hans; Brandan, Enrique
    Decorin is a member of the family of the small leucine-rich proteoglycans. In addition to its function as an extracellular matrix organizer, it has the ability to activate the epidermal growth factor receptor, and it forms complexes with various isoforms of transforming growth factor beta (TGF-beta), Decorin is expressed during skeletal muscle differentiation and is up-regulated in dystrophic muscle. In this study we investigated the role of decorin in TGF-beta -dependent inhibition of myogenesis, To probe the function of decorin during myogenesis, C2C12 myoblasts were stably transfected with a plasmid expressing antisense decorin mRNA. The re; suiting inhibition of decorin expression led to the expression of myogenin, a master transcription factor for muscle differentiation, under growth conditions and accelerated skeletal muscle differentiation as determined by the expression of creatine kinase, In contrast myogenin expression was inhibited by adenovirally induced decorin expression or by adding exogenous decorin, Reduced synthesis of decorin resulted in a 7-fold decreased sensitivity to TGF-beta -mediated inhibition of myogenin expression. In contrast, adenovirally induced decorin expression in wild type cells resulted in a 5-fold increased sensitivity to TGF-beta -mediated inhibition of myogenin expression. Transfection studies with the TGF-beta -dependent promoter of the plasminogen activator inhibitor-1 coupled with luciferase revealed that the transducing receptors for TGF-beta1 and TGF-beta2 were involved in the different responses of wild type and anti-sense decorin myoblasts, These results demonstrate that a reduction of decorin expression or of decorin availability results in a decreased responsiveness to TGF-beta. These findings strongly suggest a new role for decorin during skeletal muscle terminal differentiation by activating TGF-beta -dependent signaling pathways.