14 results on '"Benitez, Raquel"'
Search Results
2. Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell
- Author
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Alejandra Romecin, Paola, Vinyoles, Meritxell, Lopez-Millan, Belen, Diaz de la Guardia, Rafael, Atucha, Noemi M., Querol, Sergi, Bueno, Clara, Benitez, Raquel, Gonzalez-Rey, Elena, Delgado, Mario, Menendez, Pablo, [Alejandra Romecin, Paola] Josep Carreras Leukemia Res Inst, Barcelona, Spain, [Vinyoles, Meritxell] Josep Carreras Leukemia Res Inst, Barcelona, Spain, [Lopez-Millan, Belen] Josep Carreras Leukemia Res Inst, Barcelona, Spain, [Bueno, Clara] Josep Carreras Leukemia Res Inst, Barcelona, Spain, [Menendez, Pablo] Josep Carreras Leukemia Res Inst, Barcelona, Spain, [Alejandra Romecin, Paola] ISCIII, RICORS TERAV, Madrid, Spain, [Lopez-Millan, Belen] ISCIII, RICORS TERAV, Madrid, Spain, [Querol, Sergi] ISCIII, RICORS TERAV, Madrid, Spain, [Bueno, Clara] ISCIII, RICORS TERAV, Madrid, Spain, [Menendez, Pablo] ISCIII, RICORS TERAV, Madrid, Spain, [Lopez-Millan, Belen] Univ Granada, GENYO, Ctr Pfizer, Junta Andalucia Genom & Invest Oncol, Granada, Spain, [Diaz de la Guardia, Rafael] Univ Granada, GENYO, Ctr Pfizer, Junta Andalucia Genom & Invest Oncol, Granada, Spain, [Atucha, Noemi M.] Fac Med, Dept Fisiol Humana, Murcia, Spain, [Querol, Sergi] Banc Sang & Teixits, Barcelona, Spain, [Bueno, Clara] ISCIII, CIBERONC, Barcelona, Spain, [Menendez, Pablo] ISCIII, CIBERONC, Barcelona, Spain, [Benitez, Raquel] Inst Parasitol & Biomed Lopez Neyra IPBLN CSIC, Granada, Spain, [Gonzalez-Rey, Elena] Inst Parasitol & Biomed Lopez Neyra IPBLN CSIC, Granada, Spain, [Delgado, Mario] Inst Parasitol & Biomed Lopez Neyra IPBLN CSIC, Granada, Spain, [Menendez, Pablo] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain, Health Canada, Juan de la Cierva fellowship by the Spanish Ministry of Science and Innovation, and Spanish Association of Cancer Research (AECC)
- Subjects
iCasp9 switch ,Protein ,Anti-Inflammatory Agents ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,Safety switch ,BM-MSC ,Experimental colitis ,Caspase 9 ,Immunomodulation ,Extracellular Vesicles ,Colitis in vivo model ,Improve ,Humans ,WJ-MSC ,Anti-inflammatory ,Immunosuppressive Agents ,Immunosuppression ,Developmental Biology - Abstract
The financial support for this work was obtained from Health Canada (H4080-144541) to P.M. M.V. and B.L.-M. were supported by a Juan de la Cierva fellowship by the Spanish Ministry of Science and Innovation (IJCI-2017-3317) and a fellowship from the Spanish Association of Cancer Research (AECC), respectively., Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cellfree therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a “suicide gene” switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both “parental” alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs., Health Canada H4080-144541, Juan de la Cierva fellowship by the Spanish Ministry of Science and Innovation IJCI-2017-3317, Spanish Association of Cancer Research (AECC)
- Published
- 2022
3. Cortistatin regulates fibrosis and myofibroblast activation in experimental hepatotoxic¿and cholestatic¿induced liver injury.
- Author
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Ministerio de Ciencia e Innovación (España), Junta de Andalucía, Benitez, Raquel, Caro, Marta, Andrés-León, Eduardo, O'Valle, Francisco, Delgado, Mario, Ministerio de Ciencia e Innovación (España), Junta de Andalucía, Benitez, Raquel, Caro, Marta, Andrés-León, Eduardo, O'Valle, Francisco, and Delgado, Mario
- Abstract
Background and Purpose Liver fibrosis induced by chronic hepatic injury remains a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis. Experimental Approach We experimentally induced liver fibrosis in mice by chronic CCl4 exposure and bile duct ligation and evaluated the histopathological signs and fibrotic markers. Key Results Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged by hepatotoxic and cholestatic injury. Compared with wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury. Conclusion and Implications: We identify cortistatin as an endogenous molecular brake on liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that link with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various aetiologies.
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- 2022
4. Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell.
- Author
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Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Health Canada, Romecin, Paola, Vinyoles, Meritxell, López-Millán, Belén, Díaz de la Guardia, Rafael, Atucha, Noemi, Querol, Sergio, Bueno, Clara, Benitez, Raquel, González-Rey, Elena, Delgado, Mario, Menéndez, Pablo, Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Health Canada, Romecin, Paola, Vinyoles, Meritxell, López-Millán, Belén, Díaz de la Guardia, Rafael, Atucha, Noemi, Querol, Sergio, Bueno, Clara, Benitez, Raquel, González-Rey, Elena, Delgado, Mario, and Menéndez, Pablo
- Abstract
Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a "suicide gene" switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both "parental" alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs.
- Published
- 2022
5. Cortistatin regulates fibrosis and myofibroblast activation in experimental hepatotoxic‐ and cholestatic‐induced liver injury
- Author
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Benitez, Raquel, primary, Caro, Marta, additional, Andres‐Leon, Eduardo, additional, O'Valle, Francisco, additional, and Delgado, Mario, additional
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- 2022
- Full Text
- View/download PDF
6. Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells
- Author
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Delgado-Maroto, Virginia, Benitez, Raquel, Forte-Lago, Irene, Morell, Maria, Maganto-Garcia, Elena, Souza-Moreira, Luciana, O’Valle, Francisco, Duran-Prado, Mario, Lichtman, Andrew H., Gonzalez-Rey, Elena, and Delgado, Mario
- Published
- 2017
- Full Text
- View/download PDF
7. Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell
- Author
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Romecín, Paola Alejandra, primary, Vinyoles, Meritxell, additional, López-Millán, Belén, additional, de la Guardia, Rafael Diaz, additional, Atucha, Noemi M, additional, Querol, Sergi, additional, Bueno, Clara, additional, Benitez, Raquel, additional, Gonzalez-Rey, Elena, additional, Delgado, Mario, additional, and Menéndez, Pablo, additional
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- 2022
- Full Text
- View/download PDF
8. Protective Role of Cortistatin in Pulmonary Inflammation and Fibrosis
- Author
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Barriga, Margarita, Benitez, Raquel, Ferraz-de-Paula, Viviane, Garcia-Frutos, Marina, Caro, Marta, Robledo, Gema, O’Valle, Francisco4, Campos-Salinas, Jenny, Delgado, Mario, Ministerio de Economía y Competitividad (España), Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia, Innovación y Universidades (España), Delgado, Mario, and Delgado, Mario [0000-0003-1893-5982]
- Subjects
Neuropeptide ,Macrophages ,Acute lung injury ,Pulmonary inflammation ,Fibroblasts - Abstract
Background and Purpose Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and healthcare burden in the critically ill patient. There is an urgent medical need for identifying factors of susceptibility and prognosis and for designing new therapeutic tools for treating these disorders. Here, we evaluate the capacity of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo. Experimental Approach ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines and fibrotic markers were evaluated. Key Results Partially-deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis after high-exposition to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin- and ghrelin-receptors. Conclusion and Implications We identify to cortistatin as an endogenous break of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor-prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies emerge as attractive candidates to treat severe ALI/ARDS, including SARS-Cov-2-associated ARDS., This study was mainly supported by the Spanish Ministry of Science and Innovation (MICINN, grant SAF2015-67787-R). R.B. was recipient of FPI fellowship from Spanish Ministry of Science and Innovation and M.G.-F. was recipient of FPU fellowship from Spanish Ministry of Universities.V.F-P. was recipient of postdoctoral fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (12/21767-5)
- Published
- 2021
9. Protective role of cortistatin in pulmonary inflammation and fibrosis
- Author
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Barriga, Margarita, primary, Benitez, Raquel, additional, Ferraz‐de‐Paula, Viviane, additional, Garcia‐Frutos, Marina, additional, Caro, Marta, additional, Robledo, Gema, additional, O'Valle, Francisco, additional, Campos‐Salinas, Jenny, additional, and Delgado, Mario, additional
- Published
- 2021
- Full Text
- View/download PDF
10. The Neuropeptide Cortistatin Alleviates Neuropathic Pain in Experimental Models of Peripheral Nerve Injury
- Author
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Falo, Clara P., primary, Benitez, Raquel, additional, Caro, Marta, additional, Morell, Maria, additional, Forte-Lago, Irene, additional, Hernandez-Cortes, Pedro, additional, Sanchez-Gonzalez, Clara, additional, O’Valle, Francisco, additional, Delgado, Mario, additional, and Gonzalez-Rey, Elena, additional
- Published
- 2021
- Full Text
- View/download PDF
11. Protective Role of Cortistatin in Pulmonary Inflammation and Fibrosis
- Author
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Ministerio de Economía y Competitividad (España), Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia, Innovación y Universidades (España), Delgado, Mario [0000-0003-1893-5982], Barriga, Margarita, Benitez, Raquel, Ferraz-de-Paula, Viviane, Garcia-Frutos, Marina, Caro, Marta, Robledo, Gema, O’Valle, Francisco, Campos-Salinas, Jenny, Delgado, Mario, Ministerio de Economía y Competitividad (España), Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia, Innovación y Universidades (España), Delgado, Mario [0000-0003-1893-5982], Barriga, Margarita, Benitez, Raquel, Ferraz-de-Paula, Viviane, Garcia-Frutos, Marina, Caro, Marta, Robledo, Gema, O’Valle, Francisco, Campos-Salinas, Jenny, and Delgado, Mario
- Abstract
Background and Purpose Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and healthcare burden in the critically ill patient. There is an urgent medical need for identifying factors of susceptibility and prognosis and for designing new therapeutic tools for treating these disorders. Here, we evaluate the capacity of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo. Experimental Approach ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines and fibrotic markers were evaluated. Key Results Partially-deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis after high-exposition to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin- and ghrelin-receptors. Conclusion and Implications We identify to cortistatin as an endogenous break of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor-prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies emerge as attractive candidates to treat severe ALI/ARDS, including SARS-Cov-2-associated ARDS.
- Published
- 2021
12. Vasoactive Intestinal Peptide Ameliorates Acute Myocarditis and Atherosclerosis by Regulating Inflammatory and Autoimmune Responses
- Author
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Ministerio de Economía y Competitividad (España), Junta de Andalucía, Benitez, Raquel [0000-0002-0773-108X], Durán-Prado, M. [0000-0001-9652-5765], O'Valle, Francisco [0000-0001-9207-2287], González-Rey, Elena [0000-0003-3917-9020], Delgado, M. [0000-0003-1893-5982], Benitez, Raquel, Delgado-Maroto, V., Caro, Marta, Forte-Lago, Irene, Durán-Prado, Mario, O'Valle, Francisco, Lichtman, Andrew H., González-Rey, Elena, Delgado, M., Ministerio de Economía y Competitividad (España), Junta de Andalucía, Benitez, Raquel [0000-0002-0773-108X], Durán-Prado, M. [0000-0001-9652-5765], O'Valle, Francisco [0000-0001-9207-2287], González-Rey, Elena [0000-0003-3917-9020], Delgado, M. [0000-0003-1893-5982], Benitez, Raquel, Delgado-Maroto, V., Caro, Marta, Forte-Lago, Irene, Durán-Prado, Mario, O'Valle, Francisco, Lichtman, Andrew H., González-Rey, Elena, and Delgado, M.
- Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E-deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis.
- Published
- 2018
13. Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells
- Author
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González-Rey, Elena [0000-0003-3917-9020], Delgado, M. [0000-0003-1893-5982], Delgado-Maroto, V. [0000-0002-2503-5707], Souza-Moreira, L. [0000-0002-1871-4402], O'Valle, Francisco [0000-0001-9207-2287], Delgado-Maroto, V., Benitez, Raquel, Forte-Lago, Irene, Morell, M., Maganto-García, Elena, Souza-Moreira, L., O’Valle, Francisco, Durán-Prado, Mario, Lichtman, Andrew H., González-Rey, Elena, Delgado, M., González-Rey, Elena [0000-0003-3917-9020], Delgado, M. [0000-0003-1893-5982], Delgado-Maroto, V. [0000-0002-2503-5707], Souza-Moreira, L. [0000-0002-1871-4402], O'Valle, Francisco [0000-0001-9207-2287], Delgado-Maroto, V., Benitez, Raquel, Forte-Lago, Irene, Morell, M., Maganto-García, Elena, Souza-Moreira, L., O’Valle, Francisco, Durán-Prado, Mario, Lichtman, Andrew H., González-Rey, Elena, and Delgado, M.
- Abstract
Atherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases. Its role in inflammatory cardiovascular disorders is largely unexplored. The aim of this study is to investigate the potential therapeutic effects of cortistatin in two well-established preclinical models of atherosclerosis, and the molecular and cellular mechanisms involved. Systemic treatment with cortistatin reduced the number and size of atherosclerotic plaques in carotid artery, heart, aortic arch and aorta in acute and chronic atherosclerosis induced in apolipoprotein E-deficient mice fed a high-lipid diet. This effect was exerted at multiple levels. Cortistatin reduced Th1/Th17-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and lymphoid organs. Moreover, cortistatin reduced the capacity of endothelial cells to bind and recruit immune cells to the plaque and impaired the formation of foam cells by enhancing cholesterol efflux from macrophages. Cortistatin emerges as a new candidate for the treatment of the clinical manifestations of atherosclerosis
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- 2017
14. Vasoactive Intestinal Peptide Ameliorates Acute Myocarditis and Atherosclerosis by Regulating Inflammatory and Autoimmune Responses
- Author
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Elena Gonzalez-Rey, Irene Forte-Lago, Francisco O'Valle, Marta Caro, Mario Durán-Prado, Mario Delgado, Andrew H. Lichtman, Raquel Benitez, Virginia Delgado-Maroto, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Benitez, Raquel, Durán-Prado, M., O'Valle, Francisco, González-Rey, Elena, Delgado, M., Benitez, Raquel [0000-0002-0773-108X], Durán-Prado, M. [0000-0001-9652-5765], O'Valle, Francisco [0000-0001-9207-2287], González-Rey, Elena [0000-0003-3917-9020], and Delgado, M. [0000-0003-1893-5982]
- Subjects
Male ,0301 basic medicine ,Neointima ,Myocarditis ,Apolipoprotein B ,Immunology ,Vasoactive intestinal peptide ,Autoimmunity ,030204 cardiovascular system & hematology ,T-Lymphocytes, Regulatory ,Autoimmune Diseases ,Mice ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Immunology and Allergy ,Autoantibodies ,Inflammation ,Mice, Inbred BALB C ,biology ,business.industry ,Macrophages ,Myocardium ,Neuropeptides ,Autoantibody ,Muscle, Smooth ,Atherosclerosis ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Lymphatic system ,Circulatory system ,biology.protein ,Th17 Cells ,Female ,Lymph Nodes ,business ,Vasoactive Intestinal Peptide - Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E-deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis., This work was supported by the Spanish Ministry of Economy and Competitiveness and the Excellence Grant Program from the Andalusian regional government.
- Published
- 2018
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