RESUMO
RATIONALE: Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years. OBJECTIVE: We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro. METHODS AND RESULTS: A microarray was performed to analyze miRNAs in response to angiotensin II treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response on angiotensin II treatment. We identified myeloid differentiation primary response gene 88 (Myd88) as a miR-489 target to mediate the function of miR-489 in cardiac hypertrophy. Knockdown of Myd88 in cardiomyocytes and Myd88-knockout mice both showed attenuated hypertrophic responses. Furthermore, we explored the molecular mechanism by which miR-489 expression is regulated and found that an lncRNA that we named CHRF acts as an endogenous sponge of miR-489, which downregulates miR-489 expression levels. CHRF is able to directly bind to miR-489 and regulate Myd88 expression and hypertrophy. CONCLUSIONS: Our present study reveals a novel cardiac hypertrophy regulating model that is composed of CHRF, miR-489, and Myd88. The modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
Assuntos
Cardiomegalia/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Angiotensina II , Animais , Apoptose , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , Fatores de Tempo , TransfecçãoRESUMO
AIM: To investigate the effect of evodiamine (a quinolone alkaloid from the fruit of Evodia rutaecarpa) on the progression of Alzheimer's disease in SAMP8 and APP(swe)/PS1(ΔE9) transgenic mouse models. METHODS: The mice at age of 5 months were randomized into the model group, two evodiamine (50 mg·kg(-1)·d(-1) and 100 mg·kg(-1)·d(-1)) groups and an Aricept (2 mg·kg(-1)·d(-1)) group. The littermates of no-transgenic mice and senescence accelerated mouse/resistance 1 mice (SAMR1) were used as controls. After 4 weeks of treatment, learning abilities and memory were assessed using Morris water-maze test, and glucose uptake by the brain was detected using positron emission tomography/computed tomography (PET/CT). Expression levels of IL-1ß, IL-6, and TNF-α in brain tissues were detected using ELISA. Expression of COX-2 protein was determined using Western blot. RESULTS: In Morris water-maze test, evodiamine (100 mg·kg(-1)·d(-1)) significantly alleviated the impairments of learning ability and memory. Evodiamine (100 mg·kg(-1)·d(-1)) also reversed the inhibition of glucose uptake due to development of Alzheimer's disease traits in mice. Furthermore, the dose of evodiamine significantly decreased the expression of IL-1ß, IL-6, TNF-α, and COX-2 that were involved in the inflammation due to Alzheimer's disease. CONCLUSION: The results indicate that evodiamine (100 mg·kg(-1)·d(-1)) improves cognitive abilities in the transgenic models of Alzheimer's disease.