RESUMO
Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality worldwide. However, postinfarction pathogenesis remains unclear, and it is particularly important to identify new therapeutic targets. The RNA-binding motif protein RBM3 (also known as cold-inducible protein) is known to promote translation and is associated with tumor proliferation and neuroprotection. However, little is known about the biological effects of RBM3 on myocardial infarction. In the present study, we found that RBM3 expression was significantly upregulated in ischemiareperfusion (I/R) condition and downregulation of RBM3 inhibited autophagy and promoted apoptosis in cardiomyocytes. We confirmed that RBM3 interacts with Raptor to regulate the autophagy pathway. Taken together, these findings illustrate the protective effects of RBM3 against I/R-induced myocardial apoptosis through the autophagy pathway. (AU)
Assuntos
Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Aves Predatórias/metabolismo , Autofagia , Apoptose , Proteínas de Ligação a RNA , Miócitos Cardíacos/metabolismoRESUMO
Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality worldwide. However, postinfarction pathogenesis remains unclear, and it is particularly important to identify new therapeutic targets. The RNA-binding motif protein RBM3 (also known as cold-inducible protein) is known to promote translation and is associated with tumor proliferation and neuroprotection. However, little is known about the biological effects of RBM3 on myocardial infarction. In the present study, we found that RBM3 expression was significantly upregulated in ischemia-reperfusion (I/R) condition and downregulation of RBM3 inhibited autophagy and promoted apoptosis in cardiomyocytes. We confirmed that RBM3 interacts with Raptor to regulate the autophagy pathway. Taken together, these findings illustrate the protective effects of RBM3 against I/R-induced myocardial apoptosis through the autophagy pathway.
Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Proteínas de Ligação a RNA , Proteína Regulatória Associada a mTOR , Animais , Humanos , Apoptose , Autofagia , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Reperfusão , Proteínas de Ligação a RNA/metabolismo , Proteína Regulatória Associada a mTOR/metabolismoRESUMO
The exact role of autophagy in myocardial ischemia/reperfusion (I/R) injury is still controversial. Excessive or insufficient autophagy may lead to cell death. Therefore, how to regulate autophagic balance during myocardial ischemia/reperfusion is critical to the treatment of myocardial I/R injury. Raptor is an mTOR regulatory related protein and closely related to the induction of autophagy. ZNF143 is widely expressed in various cells and acts as a transcription factor, which is involved in the regulation of autophagy, cell growth and development. In this study, we aimed to explore the mechanism by which ZNF143 regulated autophagy in myocardial I/R injury and the relationship between ZNF143 and Raptor. In our results, we found that ZNF143 expression was down-regulated in myocardial I/R. Inhibition of ZNF143 expression further enhanced autophagy and restored the deficiency of autophagic flux caused by myocardial I/R, subsequently alleviating myocardial I/R injury. On the other hand, overexpression of ZNF143 up-regulated Raptor expression and reduced autophagic activity, consequently exacerbating myocardial I/R injury. Taken together, our study revealed that ZNF143 might be a key target of the regulation of autophagy and a novel therapeutic target of myocardial I/R injury.
Assuntos
Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Autofagia/genética , Humanos , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Traumatismo por Reperfusão/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury. METHODS: TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope. RESULTS: I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1ß levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion. CONCLUSIONS: Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury. Video Abstract.
Assuntos
Proteína Beclina-1/genética , Caspases Iniciadoras/genética , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Animais , Autofagia/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica/genética , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Microvasos/lesões , Microvasos/metabolismo , Microvasos/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Piroptose/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Myocardial fibrosis (MF) is an inevitable pathological process in the terminal stage of many cardiovascular diseases, often leading to serious cardiac dysfunction and even death. Currently, microRNA-29 (miR-29) is thought to be a novel diagnostic and therapeutic target of MF. Understanding the underlying mechanisms of miR-29 that regulate MF will provide a new direction for MF therapy. In the present review, we concentrate on the underlying signaling pathway of miR-29 affecting MF and the crosstalk regulatory relationship among these pathways to illustrate the complex regulatory network of miR-29 in MF. Additionally, based on our mechanistic understanding, we summarize opportunities and challenges of miR-29-based MF diagnosis and therapy.