RESUMO
Obesity often leads to obesity-related cardiac hypertrophy (ORCH), which is suppressed by zinc-induced inactivation of p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated the mechanisms by which zinc inactivates p38 MAPK to prevent ORCH. Mice (4-week old) were fed either high fat diet (HFD, 60% kcal fat) or normal diet (ND, 10% kcal fat) containing variable amounts of zinc (deficiency, normal and supplement) for 3 and 6 months. P38 MAPK siRNA and the p38 MAPK inhibitor SB203580 were used to suppress p38 MAPK activity in vitro and in vivo, respectively. HFD activated p38 MAPK and increased expression of B-cell lymphoma/CLL 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These responses were enhanced by zinc deficiency and attenuated by zinc supplement. Administration of SB203580 to HFD mice or specific siRNA in palmitate-treated cardiomyocytes eliminated the HFD and zinc deficiency activation of p38 MAPK, but did not significantly impact the expression of BCL10 and CARD9. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate-induced increased p38 MAPK activation and atrial natriuretic peptide (ANP) expression. In contrast, inhibition of p38 MAPK prevented ANP expression, but did not affect BCL10 expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate-induced up-regulation of BCL10 and phospho-p38 MAPK. HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress-mediated activation of BCL10/CARD9/p38 MAPK signalling. Zinc supplement ameliorates ORCH through activation of metallothionein to repress oxidative stress-activated BCL10 expression and p38 MAPK activation.
Assuntos
Proteína 10 de Linfoma CCL de Células B/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Cardiomegalia/tratamento farmacológico , Metalotioneína/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Cardiomegalia/etiologia , Cardiomegalia/genética , Cardiomegalia/patologia , Dieta Hiperlipídica , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Piridinas/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Zinco/administração & dosagem , Zinco/deficiênciaRESUMO
BACKGROUND: Hypereosinophilic syndrome (HES) can be fatal, particularly when eosinophils infiltrate vital organs and/or if extensive thrombosis develops. However there are no standard recommendations for the use of anticoagulant therapy of HES in the setting of thrombosis. METHODS: We herein present a case of a 46-year-old female who presented with marked peripheral eosinophilia with symptoms of multi-organ infiltration and extensive deep venous thrombosis (DVT). In this case, evaluation was carried out before the diagnosis was established, and timely standard-dose corticosteroids combined with a new oral anticoagulant (NOAC) therapy were carried out. RESULTS: These measures resulted in a rapid response and long-term disease control. CONCLUSION: Although there are no data to support which anticoagulant is preferred in this setting, this case indicates that the new oral anticoagulants may play an important role in the treatment of thrombosis in HES.