RESUMEN
Rosiglitazone is an anti-diabetic agent that raised a major controversy over its cardiovascular adverse effects. There is in vivo evidence that Rosiglitazone promotes cardiac hypertrophy by PPAR-γ-independent mechanisms. However, whether Rosiglitazone directly alters hypertrophic growth in cardiac cells is unknown. Chromatin remodeling by histone post-translational modifications has emerged as critical for many cardiomyopathies. Based on these observations, this study was initiated to investigate the cardiac hypertrophic effect of Rosiglitazone in a cellular model of primary neonatal rat cardiomyocytes (NRCM). We assessed whether the drug alters cardiac hypertrophy and its relationship with histone H3 phosphorylation. Our study showed that Rosiglitazone is a mild pro-hypertrophic agent. Rosiglitazone caused a significant increase in the release of brain natriuretic peptide (BNP) into the cell media and also increased cardiomyocytes surface area and atrial natriuretic peptide (ANP) protein expression significantly. These changes correlated with increased cardiac phosphorylation of p38 MAPK and enhanced phosphorylation of H3 at serine 10 globally and at one cardiac hypertrophic gene locus. These results demonstrate that Rosiglitazone causes direct cardiac hypertrophy in NRCM and alters H3 phosphorylation status. They suggest a new mechanism of Rosiglitazone cardiotoxicity implicating chromatin remodeling secondary to H3 phosphorylation, which activate the fetal cardiac gene program.
Asunto(s)
Cardiomegalia/inducido químicamente , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Fibrinolíticos/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Tiazolidinedionas/toxicidad , Animales , Factor Natriurético Atrial/metabolismo , Epigénesis Genética , Femenino , Fibrinolíticos/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Ratas , Ratas Sprague-Dawley , Rosiglitazona , Tiazolidinedionas/administración & dosificación , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. RESULTS: We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. CONCLUSION: Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM.
Asunto(s)
Cardiomiopatía Dilatada/genética , Insuficiencia Cardíaca/genética , Proteínas Musculares/genética , Proteínas Ligasas SKP Cullina F-box/genética , Secuencia de Aminoácidos/genética , Autofagia/genética , Cardiomiopatía Dilatada/patología , Citoesqueleto/genética , Citoesqueleto/metabolismo , Regulación de la Expresión Génica , Ligamiento Genético , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/patología , Humanos , Proteínas Musculares/metabolismo , Mutación Missense/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Sarcómeros/genética , Sarcómeros/metabolismoRESUMEN
The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions. However, Acp1(-/-) mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the postnatal stage, and increased in the adult mouse failing heart. We also show that LMPTP expression increases in end-stage heart failure in humans. Consistent with their protected phenotype, Acp1(-/-) mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of fibrotic genes. Transcriptional profiling and analysis of molecular signalling show that the resistance of Acp1(-/-) mice to pathological cardiac stress correlates with marginal re-expression of fetal cardiac genes, increased insulin receptor beta phosphorylation, as well as PKA and ephrin receptor expression, and inactivation of the CaMKIIδ pathway. Our data show that ablation of Lmptp inhibits pathological cardiac remodelling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of human heart failure.