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J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108


Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

J Biol Chem ; 280(9): 8606-16, 2005 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-15623512


The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed to be the major factors that contribute to malaria pathogenesis through their ability to induce proinflammatory responses. In this study we identified the receptors for P. falciparum GPI-induced cell signaling that leads to proinflammatory responses and studied the GPI structure-activity relationship. The data show that GPI signaling is mediated mainly through recognition by TLR2 and to a lesser extent by TLR4. The activity of sn-2-lyso-GPIs is comparable with that of the intact GPIs, whereas the activity of Man(3)-GPIs is about 80% that of the intact GPIs. The GPIs with three (intact GPIs and Man(3)-GPIs) and two fatty acids (sn-2-lyso-GPIs) appear to differ considerably in the requirement of the auxiliary receptor, TLR1 or TLR6, for recognition by TLR2. The former are preferentially recognized by TLR2/TLR1, whereas the latter are favored by TLR2/TLR6. However, the signaling pathways initiated by all three GPI types are similar, involving the MyD88-dependent activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 and NF-kappaB-signaling pathways. The signaling molecules of these pathways differentially contribute to the production of various cytokines and nitric oxide (Zhu, J., Krishnegowda, G., and Gowda, D. C. (2004) J. Biol. Chem. 280, 8617-8627). Our data also show that GPIs are degraded by the macrophage surface phospholipases predominantly into inactive species, indicating that the host can regulate GPI activity at least in part by this mechanism. These results imply that macrophage surface phospholipases play important roles in the GPI-induced innate immune responses and malaria pathogenesis.

Glicosilfosfatidilinositóis/química , Inflamação , Macrófagos/metabolismo , Macrófagos/parasitologia , Plasmodium falciparum/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos de Diferenciação/metabolismo , Western Blotting , Medula Óssea/metabolismo , Carboidratos/química , Linhagem Celular , Separação Celular , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Ouro/química , Humanos , Metabolismo dos Lipídeos , Espectrometria de Massas , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide , Fosfolipases/metabolismo , Polissacarídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Receptor 1 Toll-Like , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptor 6 Toll-Like , Receptores Toll-Like , Fator de Necrose Tumoral alfa/metabolismo