MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts
| Autor: | Jiangtong Peng, Xiaohong Wang, Qinghua Han, Liwang Yang, Xingjiang Mu, Kai-Jiang Yu, Dongze Qin, Kobina Essandoh, Guo-Chang Fan, Tianqing Peng, Yutian Li, Rui-Tao Wang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Programmed cell death Indoles Necrosis Necroptosis Ischemia Myocardial Reperfusion Injury IκB kinase 030204 cardiovascular system & hematology Biology Pharmacology Biochemistry Receptors Tumor Necrosis Factor Mice 03 medical and health sciences 0302 clinical medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Receptor Molecular Biology Mice Knockout Imidazoles Wild type Molecular Bases of Disease Cell Biology medicine.disease I-kappa B Kinase MicroRNAs 030104 developmental biology Receptors Tumor Necrosis Factor Type I Immunology medicine.symptom |
| Zdroj: | Journal of Biological Chemistry. 291:20247-20259 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m116.732735 |
| Popis: | Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R-triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223-5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IκB kinase α, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease. |
| Databáze: | OpenAIRE |
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