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Soft tissue sarcomas accounts for 1-2% of adult malignancies. Undifferentiated pleomorphic sarcoma (UPS) is a rare subtype that lack immunohistochemical markers for a specific definition. About 18% of sarcomas are at a locally advanced stage, often requiring several cycles of chemotherapy and radiotherapy, in addition to surgery. For a young woman, this can mean delaying pregnancies with a high risk of therapy-induced ovarian damage. For this reason, proper counseling on fertility preservation plays a key role. In addition, all women of childbearing age with cancer, should be informed about the importance of planning a pregnancy to improve maternal and neonatal outcomes. We report a rare case of a 40-year-old woman with a UPS who, during CT scan after chemotherapy to decide on surgery, find out she was pregnant. After counseling, the patient decides to go ahead with the pregnancy.
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Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as ß2-adrenergic receptor (ß2-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by ß2-ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a ß2-AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.
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Regulador de Condutância Transmembrana em Fibrose Cística , Fosfatidilinositol 3-Quinase , Animais , Classe Ib de Fosfatidilinositol 3-Quinase , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Inflamação , Camundongos , Peptídeos/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.
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Cystic fibrosis (CF) is the most common amongst rare genetic diseases, affecting more than 70.000 people worldwide. CF is characterized by a dysfunctional chloride channel, termed cystic fibrosis conductance regulator (CFTR), which leads to the production of a thick and viscous mucus layer that clogs the lungs of CF patients and traps pathogens, leading to chronic infections and inflammation and, ultimately, lung damage. In recent years, the use of peptides for the treatment of respiratory diseases, including CF, has gained growing interest. Therapeutic peptides for CF include antimicrobial peptides, inhibitors of proteases, and modulators of ion channels, among others. Peptides display unique features that make them appealing candidates for clinical translation, like specificity of action, high efficacy, and low toxicity. Nevertheless, the intrinsic properties of peptides, together with the need of delivering these compounds locally, e.g. by inhalation, raise a number of concerns in the development of peptide therapeutics for CF lung disease. In this review, we discuss the challenges related to the use of peptides for the treatment of CF lung disease through inhalation, which include retention within mucus, proteolysis, immunogenicity and aggregation. Strategies for overcoming major shortcomings of peptide therapeutics will be presented, together with recent developments in peptide design and optimization, including computational analysis and high-throughput screening.
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Fibrose Cística/tratamento farmacológico , Peptídeos/uso terapêutico , Humanos , Peptídeos/químicaRESUMO
Cachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve our understanding of the underlying mechanisms. Increasing evidence links the wasting of the cardiac and skeletal muscles to metabolic alterations, primarily increased energy expenditure, and to increased proteolysis, ensuing from activation of the major proteolytic machineries of the cell, including ubiquitin-dependent proteolysis and autophagy. This review aims at providing an overview of the key mechanisms of cancer cachexia, with a major focus on those that are shared by the skeletal and cardiac muscles.
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Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.
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Antraciclinas , Neoplasias , Cardiotoxicidade , Humanos , Fatores de RiscoRESUMO
Significance: The cardiac side effects of hematological treatments are a major issue of the growing population of cancer survivors, often affecting patient survival even more than the tumor for which the treatment was initially prescribed. Among the most cardiotoxic drugs are anthracyclines (ANTs), highly potent antitumor agents, which still represent a mainstay in the treatment of hematological and solid tumors. Unfortunately, diagnosis, prevention, and treatment of cardiotoxicity are still unmet clinical needs, which call for a better understanding of the molecular mechanism behind the pathology. Recent Advances: This review article will discuss recent findings on the pathomechanisms underlying the cardiotoxicity of ANTs, spanning from DNA and mitochondrial damage to calcium homeostasis, autophagy, and apoptosis. Special emphasis will be given to the role of reactive oxygen species and their interplay with major signaling pathways. Critical Issues: Although new promising therapeutic targets and new drugs have started to be identified, their efficacy has been mainly proven in preclinical studies and requires clinical validation. Future Directions: Future studies are awaited to confirm the relevance of recently uncovered targets, as well as to identify new druggable pathways, in more clinically relevant models, including, for example, human induced pluripotent stem cell-derived cardiomyocytes.
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Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Cardiotoxicidade/complicações , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
AIMS: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. METHODS AND RESULTS: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2 O2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. CONCLUSIONS: Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
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Amidas/farmacologia , Doxorrubicina/efeitos adversos , Miócitos Cardíacos , Estresse Oxidativo/efeitos dos fármacos , Fenilalanina/farmacologia , Animais , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Butiratos/farmacologia , Ácido Butírico/metabolismo , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Ecocardiografia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Resultado do TratamentoAssuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Neoplasias/tratamento farmacológico , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , LongevidadeRESUMO
BACKGROUND: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy. OBJECTIVE: The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs. METHODS: The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted. RESULTS: Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release. CONCLUSION: Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.
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Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Crotoxina/uso terapêutico , Fibrose Cística/terapia , Peptídeos/uso terapêutico , Peptídeo Intestinal Vasoativo/uso terapêutico , alfa 1-Antitripsina/uso terapêutico , Administração por Inalação , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Canais Epiteliais de Sódio/metabolismo , Humanos , Muco/metabolismo , Mutação/genéticaRESUMO
PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
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Asma/tratamento farmacológico , Derivados de Benzeno/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ésteres/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase , Fibrose Pulmonar/tratamento farmacológico , Administração por Inalação , Animais , Asma/induzido quimicamente , Asma/patologia , Derivados de Benzeno/administração & dosagem , Bleomicina/toxicidade , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Ésteres/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologiaRESUMO
BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.
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Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cardiotoxicidade , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Citoproteção , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Feminino , Genes erbB-2 , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/patologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Mutação , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMO
The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease. In this review, we briefly summarize the role of the PI3K/AKT/mTOR pathway in cell proliferation by comparing the effect of alterations in PI3K enzymes in different tissues. In particular, we discuss the most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades.
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Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.
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Caquexia/etiologia , Caquexia/fisiopatologia , Modelos Animais de Doenças , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Proteína Oncogênica tpr-met/genética , Animais , Caquexia/diagnóstico , Ativação Enzimática , Insuficiência Cardíaca/diagnóstico , Humanos , Camundongos , Camundongos Transgênicos , Proteína Oncogênica tpr-met/metabolismoRESUMO
Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity.
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Proliferação de Células , Fator de Crescimento de Hepatócito/metabolismo , Fator de Transcrição PAX7/metabolismo , Sarcoma/patologia , Animais , Humanos , Camundongos Transgênicos , Fator de Transcrição PAX7/genética , Sarcoma/genéticaRESUMO
Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.
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Cardiomegalia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/genética , Linhagem Celular , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Junções Comunicantes/metabolismo , Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Camundongos , Camundongos Transgênicos , Niacinamida/farmacologia , Fenótipo , Proteínas Proto-Oncogênicas c-met/genética , Remodelação Ventricular/genéticaRESUMO
Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFß1 (transforming growth factor ß1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.
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Vasos Sanguíneos/enzimologia , Doenças Cardiovasculares/enzimologia , Fator de Crescimento de Hepatócito/metabolismo , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Remodelação Vascular , Remodelação Ventricular , Animais , Apoptose , Autofagia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Fibrose , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/uso terapêutico , Humanos , Tolerância Imunológica , Inflamação/enzimologia , Inflamação/patologia , Inflamação/prevenção & controle , Terapia de Alvo Molecular , Miocárdio/imunologia , Miocárdio/patologia , Neovascularização Fisiológica , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-met/genética , Regeneração , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Activation of the hepatocyte growth factor/Met receptor is involved in muscle regeneration, through promotion of proliferation and inhibition of differentiation in myogenic stem cells (MSCs). We previously described that the specific expression of an oncogenic version of the Met receptor (Tpr-Met) in terminally-differentiated skeletal muscle causes muscle wasting in vivo. Here, we induced Tpr-Met in differentiated myotube cultures derived from the transgenic mouse. These cultures showed a reduced protein level of myosin heavy chain (MyHC), increased phosphorylation of Erk1,2 MAPK, the formation of giant sacs of myonuclei and the collapse of elongated myotubes. Treatment of the cultures with an inhibitor of the MAPK kinase pathway or with an inhibitor of the proteasome increased the expression levels of MyHC. In addition, the inhibition of the MAPK kinase pathway prevented the formation of myosacs and myotube collapse. Finally, we showed that induction of Tpr-Met in primary myotubes was unable to produce endoreplication in their nuclei. In conclusion, our data indicate that multinucleated, fused myotubes may be forced to disassemble their contractile apparatus by the Tpr-Met oncogenic factor, but they resist the stimulus toward the reactivation of the cell cycle.
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Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) play important roles in myocardial function both in physiological and pathological situations. In the developing heart, HGF influences cardiomyocyte proliferation and differentiation. In the adult, HGF/Met signaling controls heart homeostasis and prevents oxidative stress in normal cardiomyocytes. Thus, the possible cardiotoxicity of current Met-targeted anti-cancer therapies has to be taken in consideration. In the injured heart, HGF plays important roles in cardioprotection by promoting: (1) prosurvival (anti-apoptotic and anti-autophagic) effects in cardiomyocytes, (2) angiogenesis, (3) inhibition of fibrosis, (4) anti-inflammatory and immunomodulatory signals, and (5) regeneration through activation of cardiac stem cells. Furthermore, we discuss the putative role of elevated HGF as prognostic marker of severity in patients with cardiac diseases. Finally, we examine the potential of HGF-based molecules as new therapeutic tools for the treatment of cardiac diseases.