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J Mol Cell Cardiol ; 85: 117-26, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26031702


AIM OF THE STUDY: Capillary/myocyte mismatch is a hallmark of maladaptive myocardial hypertrophy, but the exact mechanisms of this phenomenon remain unknown. We therefore aimed to evaluate the role of calcineurin A in the regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a calcineurin overexpressing mouse model of myocardial hypertrophy. METHODS AND RESULTS: Mice overexpressing calcineurin A (CnATg) showed persistent upregulation of HIF-1 alpha protein without evidence of a reduction in capillary density despite progressive myocardial hypertrophy. Likewise, overexpression of calcineurin A in isolated cardiomyocytes induced upregulation of HIF-1 alpha protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent mechanisms were responsible for increased HIF-1 alpha levels. In addition, inhibition of HSP90 via the HSP90-inhibitor 17-AAG or siRNA abolished calcineurin A-induced upregulation of HIF-1 alpha. Consequently, upregulation of HIF-1 alpha target genes like VEGF-A, BNIP-3 or PGK-1 was also inhibited by either 17-AAG or siRNA directed against HSP90. Finally, when CnATg mice were treated with 17-AAG, they demonstrated reduced left ventricular function and capillary density. CONCLUSIONS: We describe here for the first time that overexpression of the phosphatase calcineurin A prevents the development of a capillary/myocyte mismatch despite progressive myocardial hypertrophy. This effect was mediated by HSP-90 induced stabilization of HIF-1 alpha. Further work is needed to understand this unexpected cardioprotective effect of calcineurin A.

Calcineurina/metabolismo , Cardiomegalia/metabolismo , Proteínas de Choque Térmico HSP90/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Vasos Coronários/patologia , Regulação para Baixo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/patologia , Fatores de Transcrição NFATC/metabolismo , Estabilidade Proteica , Ratos Wistar , Transcrição Genética
Mediators Inflamm ; 2014: 131950, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24692845


BACKGROUND: TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. AIM OF THE STUDY: To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. RESULTS: TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS) in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14-/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14+/+). Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. CONCLUSIONS: TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.

Infarto do Miocárdio/complicações , Fatores de Necrose Tumoral/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Citocina TWEAK , Ecocardiografia , Regulação da Expressão Gênica , Coração/fisiologia , Humanos , Masculino , Camundongos , Infarto do Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fosforilação Oxidativa , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteínas Recombinantes/metabolismo
Clin Res Cardiol ; 100(10): 879-85, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21479966


Soluble TWEAK is a member of the TNF-alpha family of cytokines that has been shown to predict mortality in patients with heart failure. Pulmonary artery hypertension is a devastating disease, in which right ventricular function has been shown to be the major determinant of prognosis. In this hypothesis-generating study, we sought to evaluate the potential usefulness of sTWEAK in the prediction of disease severity in patients with pulmonary artery hypertension. We therefore conducted a retrospective analysis of sTWEAK serum levels in 95 stable patients with PAH. For all patients data on hemodynamic parameters, biomarkers and functional exercise tests were available. Compared to controls, patients with PAH showed significantly decreased levels of sTWEAK [median 314 pg/ml (interquartile range 217-473 pg/ml) vs. 405 (321-496 pg/ml); PAH vs. controls; P < 0.0001]. Soluble TWEAK levels were inversely correlated with NYHA class, pulmonary artery pressure, pulmonary vascular resistance, NT-proBNP, and troponin T levels and directly correlated with cardiac index, reduced 6-min walk test distances, and peak oxygen consumption. ROC curve analysis of sTWEAK levels in PAH patients revealed a cutoff value of 306 pg/ml for sTWEAK to be predictive of a reduced exercise capacity (6-min walk test <300 m) in patients with PAH with a similar predictive value compared to NT-proBNP. Intraindividual serial evaluation of sTWEAK revealed the potential of sTWEAK as follow-up marker in patients with PAH. In our hypothesis-generating study, sTWEAK was closely correlated to hemodynamic, functional, and serological indices of outcome in patients with PAH. Further prospective studies are needed to determine the role of sTWEAK as potential biomarker in patients with PAH.

Tolerância ao Exercício , Hemodinâmica , Hipertensão Pulmonar/diagnóstico , Fatores de Necrose Tumoral/sangue , Biomarcadores/sangue , Pressão Sanguínea , Citocina TWEAK , Regulação para Baixo , Teste de Esforço , Hipertensão Pulmonar Primária Familiar , Feminino , Alemanha , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Consumo de Oxigênio , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Prognóstico , Artéria Pulmonar/fisiopatologia , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Troponina T/sangue , Resistência Vascular