title: MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts.
abstract: 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.
authors: From the Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Dongze
authors: D
authors: Qin
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Xiaohong
authors: X
authors: Wang
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Yutian
authors: Y
authors: Li
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Liwang
authors: L
authors: Yang
authors: Department of Intensive Care Unit, The Third Affiliated Hospital of Harbin Medical University, Heilongjiang 150081, China, and.
authors: Ruitao
authors: R
authors: Wang
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Jiangtong
authors: J
authors: Peng
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Kobina
authors: K
authors: Essandoh
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors: Xingjiang
authors: X
authors: Mu
authors: Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada.
authors: Tianqing
authors: T
authors: Peng
authors: From the Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors: Qinghua
authors: Q
authors: Han
authors: Department of Intensive Care Unit, The Third Affiliated Hospital of Harbin Medical University, Heilongjiang 150081, China, and.
authors: Kai-Jiang
authors: KJ
authors: Yu
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, fangg@ucmail.uc.edu.
authors: Guo-Chang
authors: GC
authors: Fan
mesh_terms: D000818:Animals; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000235:genetics
chemical_list: D007093:Imidazoles; D007211:Indoles; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; C485251:Tnfrsf21 protein, mouse; C507699:necrostatin-1; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase
keywords: inflammasome; ischemia; microRNA (miRNA); myocardial infarction; necrosis (necrotic death)