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      Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

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          Abstract

          We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7 -/- mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7 -/- hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K + currents I to and I K1 were profoundly reduced in Alk7 -/- ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of I to carrying channel) and KCHIP2 (a key accessory subunit of I to carrying channel), was markedly decreased in Alk7 -/- hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K + currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia.

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          Most cited references41

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          Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

          Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.
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            Genetic analysis of the mammalian transforming growth factor-beta superfamily.

            Members of the TGF-beta superfamily, which includes TGF-betas, growth differentiation factors, bone morphogenetic proteins, activins, inhibins, and glial cell line-derived neurotrophic factor, are synthesized as prepropeptide precursors and then processed and secreted as homodimers or heterodimers. Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions. Many studies have reported the characterization of knockout and knock-in transgenic mice as well as humans or other mammals with naturally occurring genetic mutations in superfamily members or their regulatory proteins. These investigations have revealed that TGF-beta superfamily ligands, receptors, SMADs, and upstream and downstream regulators function in diverse developmental and physiological pathways. This review attempts to collate and integrate the extensive body of in vivo mammalian studies produced over the last decade.
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              Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1.

              Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl-2 expression and downregulating Bax, caspase-3 and cleaved caspase-3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R-induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 February 2016
                2016
                : 11
                : 2
                : e0149205
                Affiliations
                [001]Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China, 238 Jiefang Road, Wuchang District, Wuhan 430060, Hubei Province, China
                Georgia State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CH. Performed the experiments: SY XW HC YT HH. Analyzed the data: SY XW HC YT. Contributed reagents/materials/analysis tools: CH YT. Wrote the paper: SY.

                Article
                PONE-D-15-41028
                10.1371/journal.pone.0149205
                4755580
                26882027
                52644db6-ca2b-4e1f-8f26-8e8248aea6a3
                © 2016 Ying 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
                : 16 September 2015
                : 28 January 2016
                Page count
                Figures: 4, Tables: 3, Pages: 14
                Funding
                This study is supported by funding from The National Science Technology Support Plan (Grant No. 2011BAI11B12) and the National Natural Science Foundation of China (Grant No. 81370282). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Medicine and Health Sciences
                Cardiology
                Arrhythmia
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Action Potentials
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Action Potentials
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Action Potentials
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Action Potentials
                Biology and Life Sciences
                Neuroscience
                Neurophysiology
                Action Potentials
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Electrophysiological Techniques
                Cardiac Electrophysiology
                Electrocardiography
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Electrophysiological Techniques
                Cardiac Electrophysiology
                Engineering and Technology
                Signal Processing
                Signal Filtering
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Cardiac Ventricles
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Cardiac Ventricles
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                All relevant data are within the paper and its Supporting Information files.

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