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      M 3 Subtype of Muscarinic Acetylcholine Receptor Promotes Cardioprotection via the Suppression of miR-376b-5p

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          Abstract

          The M 3 subtype of muscarinic acetylcholine receptors (M 3-mAChR) plays a protective role in myocardial ischemia and microRNAs (miRNAs) participate in many cardiac pathophysiological processes, including ischemia-induced cardiac injury. However, the role of miRNAs in M 3-mAChR mediated cardioprotection remains unexplored. The present study was designed to identify miRNAs that are involved in cardioprotective effects of M 3-mAChR against myocardial ischemia and elucidate the underlying mechanisms. We established rat model of myocardial ischemia and performed miRNA microarray analysis to identify miRNAs involved in the cardioprotection of M 3-mAChR. In H9c2 cells, the viability, intracellular free Ca 2+ concentration ([Ca 2+]i), intracellular reactive oxygen species (ROS), miR-376b-5p expression level, brain derived neurophic factor (BDNF) and nuclear factor kappa-B (NF-κB) levels were measured. Our results demonstrated that M 3-mAChR protected myocardial ischemia injury. Microarray analysis and qRT-PCR revealed that miR-376b-5p was significantly up-regulated in ischemic heart tissue and the M 3-mAChRs agonist choline reversed its up-regulation. In vitro, miR-376b-5p promoted H 2O 2-induced H9c2 cell injuries measured by cells viability, [Ca 2+]i and ROS. Western blot and luciferase assay identified BDNF as a direct target of miR-376b-5p. M 3-mAChR activated NF-κB and thereby inhibited miR-376b-5p expression. Our data show that a novel M 3-mAChR/NF-κB/miR-376b-5p/BDNF axis plays an important role in modulating cardioprotection. MiR-376b-5p promotes myocardial ischemia injury possibly by inhibiting BDNF expression and M 3-mAChR provides cardioprotection at least partially mediated by the downregulation of miR-376b-5p through NF-κB. These findings provide new insight into the potential mechanism by which M 3-mAChR provides cardioprotection against myocardial ischemia injury.

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          Most cited references44

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          The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2.

          MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
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            Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning.

            Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.
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              MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury.

              MicroRNAs (miRs) participate in many cardiac pathophysiological processes, including ischemia/reperfusion (I/R)-induced cardiac injury. Recently, we and others observed that miR-494 was downregulated in murine I/R-injured and human infarcted hearts. However, the functional consequence of miR-494 in response to I/R remains unknown. We generated a mouse model with cardiac-specific overexpression of miR-494. Transgenic hearts and wild-type hearts from multiple lines were subjected to global no-flow I/R with the Langendorff system. Transgenic hearts exhibited improved recovery of contractile performance over the reperfusion period. This improvement was accompanied by remarkable decreases in both lactate dehydrogenase release and the extent of apoptosis in transgenic hearts compared with wild-type hearts. In addition, myocardial infarction size was significantly reduced in transgenic hearts on I/R in vivo compared with wild-type hearts. Similarly, short-term overexpression of miR-494 in cultured adult cardiomyocytes demonstrated an inhibition of caspase-3 activity and reduced cell death on simulated I/R. In vivo treatment with antisense oligonucleotide miR-494 increased I/R-triggered cardiac injury relative to the administration of mutant antisense oligonucleotide miR-494 and saline controls. We further identified that 3 proapoptotic proteins (PTEN, ROCK1, and CaMKIIδ) and 2 antiapoptotic proteins (FGFR2 and LIF) were authentic targets for miR-494. Importantly, the Akt-mitochondrial signaling pathway was activated in miR-494-overexpressing myocytes. Our findings suggest that although miR-494 targets both proapoptotic and antiapoptotic proteins, the ultimate consequence is activation of the Akt pathway, leading to cardioprotective effects against I/R-induced injury. Thus, miR-494 may constitute a new therapeutic agent for the treatment of ischemic heart disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                2 March 2012
                : 7
                : 3
                : e32571
                Affiliations
                [1 ]Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
                [2 ]Department of Anesthesiology of the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
                [3 ]Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
                University of Oldenburg, Germany
                Author notes

                Conceived and designed the experiments: YL ZD. Performed the experiments: ZP KF HZ YF JX FG YG HQ YH SW YZ NW RH. Analyzed the data: ZP YH YG YL. Wrote the paper: ZP YG YL.

                Article
                PONE-D-11-24064
                10.1371/journal.pone.0032571
                3292572
                22396777
                ceb67848-88a3-4941-8ff6-433ccd551b4e
                Pan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 December 2011
                : 27 January 2012
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                Model Organisms
                Animal Models
                Molecular Cell Biology
                Signal Transduction
                Chemistry
                Chemical Biology
                Medicine
                Cardiovascular

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