RESUMEN
Atypical antipsychotic (AA) medications including risperidone (RIS) and olanzapine (OLAN) are FDA approved for the treatment of psychiatric disorders including schizophrenia, bipolar disorder and depression. Clinical side effects of AA medications include obesity, insulin resistance, dyslipidemia, hypertension and increased cardiovascular disease risk. Despite the known pharmacology of these AA medications, the mechanisms contributing to adverse metabolic side-effects are not well understood. To evaluate drug-associated effects on the heart, we assessed changes in the cardiac proteomic signature in mice administered for 4 weeks with clinically relevant exposure of RIS or OLAN. Using proteomic and gene enrichment analysis, we identified differentially expressed (DE) proteins in both RIS- and OLAN-treated mouse hearts (p < 0.05), including proteins comprising mitochondrial respiratory complex I and pathways involved in mitochondrial function and oxidative phosphorylation. A subset of DE proteins identified were further validated by both western blotting and quantitative real-time PCR. Histological evaluation of hearts indicated that AA-associated aberrant cardiac gene expression occurs prior to the onset of gross pathomorphological changes. Additionally, RIS treatment altered cardiac mitochondrial oxygen consumption and whole body energy expenditure. Our study provides insight into the mechanisms underlying increased patient risk for adverse cardiac outcomes with chronic treatment of AA medications.
Asunto(s)
Antipsicóticos/farmacología , Miocardio/metabolismo , Risperidona/farmacología , Animales , Ácidos Grasos no Esterificados/sangre , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Factores de Riesgo de Enfermedad Cardiaca , Masculino , Ratones Endogámicos C57BL , Miocardio/patología , Olanzapina/farmacología , Consumo de Oxígeno , ProteómicaRESUMEN
Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.
Asunto(s)
Antipsicóticos/toxicidad , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Olanzapina/toxicidad , Proteoma/metabolismo , Risperidona/toxicidad , Animales , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/etiología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Proteoma/genéticaRESUMEN
Cardiovascular disease is the leading cause of morbidity and mortality in the Western world owing to the limited regenerative capacity of the mammalian cardiovascular system. In lieu of new muscle synthesis, the human heart replaces necrotic tissue with deposition of a noncontractile scar. By contrast, the adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte (CM) creation and scar tissue removal when challenged with an acute injury. In these studies, we examined the contributions of the dynamically regulated microRNA miR-101a during adult zebrafish heart regeneration. We demonstrate that miR-101a expression is rapidly depleted within 3 days post-amputation (dpa) but is highly upregulated by 7-14 dpa, before returning to uninjured levels at the completion of the regenerative process. Employing heat-inducible transgenic strains and antisense oligonucleotides, we demonstrate that decreases in miR-101a levels at the onset of cardiac injury enhanced CM proliferation. Interestingly, prolonged suppression of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue clearance. Upregulation of miR-101a expression between 7 and 14 dpa is essential to stimulate removal of the scar. Through a series of studies, we identified the proto-oncogene fosab (cfos) as a potent miR-101a target gene, stimulator of CM proliferation, and inhibitor of scar tissue removal. Importantly, combinatorial depletion of fosab and miR-101a activity rescued defects in scar tissue clearance mediated by miR-101a inhibition alone. In summation, our studies indicate that the precise temporal modulation of the miR-101a/fosab genetic axis is crucial for coordinating CM proliferation and scar tissue removal during zebrafish heart regeneration.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Corazón/fisiología , MicroARNs/genética , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas de Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Animales , Animales Modificados Genéticamente , Sistema Cardiovascular , Proliferación Celular , Cicatriz/patología , Perfilación de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Miocitos Cardíacos/citología , Necrosis , Oligonucleótidos Antisentido/genética , Proto-Oncogenes Mas , Regeneración/fisiología , Factores de TiempoRESUMEN
The inability to effectively stimulate cardiomyocyte proliferation remains a principle barrier to regeneration in the adult human heart. A tightly regulated, acute inflammatory response mediated by a range of cell types is required to initiate regenerative processes. Prostaglandin E2 (PGE2), a potent lipid signaling molecule induced by inflammation, has been shown to promote regeneration and cell proliferation; however, the dynamics of PGE2 signaling in the context of heart regeneration remain underexplored. Here, we employ the regeneration-competent zebrafish to characterize components of the PGE2 signaling circuit following cardiac injury. In the regenerating adult heart, we documented an increase in PGE2 levels, concurrent with upregulation of cox2a and ptges, two genes critical for PGE2 synthesis. Furthermore, we identified the epicardium as the most prominent site for cox2a expression, thereby suggesting a role for this tissue as an inflammatory mediator. Injury also drove the opposing expression of PGE2 receptors, upregulating pro-restorative ptger2a and downregulating the opposing receptor ptger3. Importantly, treatment with pharmacological inhibitors of Cox2 activity suppressed both production of PGE2, and the proliferation of cardiomyocytes. These results suggest that injury-induced PGE2 signaling is key to stimulating cardiomyocyte proliferation during regeneration.
Asunto(s)
Dinoprostona/metabolismo , Lesiones Cardíacas/metabolismo , Corazón/fisiología , Regeneración , Animales , Animales Modificados Genéticamente , Proliferación Celular , Regulación hacia Abajo , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Hibridación in Situ , Inflamación , Lípidos/química , Miocitos Cardíacos/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it's active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly.
Asunto(s)
Antipsicóticos/efectos adversos , Inmunosupresores/efectos adversos , Risperidona/efectos adversos , Animales , Antipsicóticos/farmacología , Humanos , Inmunosupresores/farmacología , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteómica/métodos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/inmunología , Risperidona/farmacología , Programas InformáticosRESUMEN
Atypical antipsychotic (AA) drugs, including risperidone (RIS), are used to treat schizophrenia, bipolar disorder, and autism, and are prescribed off-label for other mental health issues. AA drugs are associated with severe metabolic side effects of obesity and type 2 diabetes. Cross-sectional and longitudinal data also show that risperidone causes bone loss and increases fracture risk in both men and women. There are several potential mechanisms of bone loss from RIS. One is hypogonadism due to hyperprolactinemia from dopamine receptor antagonism. However, many patients have normal prolactin levels; moreover we demonstrated that bone loss from RIS in mice can be blocked by inhibition of ß-adrenergic receptor activation with propranolol, suggesting the sympathetic nervous system (SNS) plays a pathological role. Further, when, we treated ovariectomized (OVX) and sham operated mice daily for 8weeks with RIS or vehicle we demonstrated that RIS causes significant trabecular bone loss in both sham operated and OVX mice. RIS directly suppressed osteoblast number in both sham and OVX mice, but increased osteoclast number and surface in OVX mice alone, potentially accounting for the augmented bone loss. Thus, hypogonadism alone cannot explain RIS induced bone loss. In the current study, we show that dopamine and RIS are present in the bone marrow compartment and that RIS can exert its effects directly on bone cells via dopamine receptors. Our findings of both direct and indirect effects of AA drugs on bone are relevant for current and future clinical and translational studies investigating the mechanism of skeletal changes from AA drugs.