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Heart RNA Decay

Anyu Zhou, An Xie, Tae Yun Kim, Hong Liu, Guangbin Shi, Gyeoung-Jin Kang, Ning Jiang, Man Liu, Euy-Myoung Jeong, Bum-Rak Choi, Samuel C Dudley
BACKGROUND: Downregulated sodium currents in heart failure (HF) have been linked to increased arrhythmic risk. Reduced expression of the messenger RNA (mRNA)-stabilizing protein ELAVL1/HuR may be responsible for the downregulation of sodium channel gene SCN5A mRNA. OBJECTIVE: The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF. METHODS: Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of SCN5A...
February 16, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Maria Warnefors, Katharina Mössinger, Jean Halbert, Tania Studer, John L VandeBerg, Isa Lindgren, Amir Fallahshahroudi, Per Jensen, Henrik Kaessmann
Sexual dimorphism depends on sex-biased gene expression, but the contributions of microRNAs (miRNAs) have not been globally assessed. We therefore produced an extensive small RNA sequencing data set to analyze male and female miRNA expression profiles in mouse, opossum, and chicken. Our analyses uncovered numerous cases of somatic sex-biased miRNA expression, with the largest proportion found in the mouse heart and liver. Sex-biased expression is explained by miRNA-specific regulation, including sex-biased chromatin accessibility at promoters, rather than piggybacking of intronic miRNAs on sex-biased protein-coding genes...
December 2017: Genome Research
Qiuming Gong, Zhengfeng Zhou
Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-à-go-go related gene (hERG), which encodes the Kv11.1 potassium channel in the heart. Over 30% of identified LQT2 mutations are nonsense or frameshift mutations that introduce premature termination codons (PTCs). Contrary to intuition, the predominant consequence of LQT2 nonsense and frameshift mutations is not the production of truncated proteins, but rather the degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD), an RNA surveillance mechanism that selectively eliminates the mRNA transcripts that contain PTCs...
2018: Methods in Molecular Biology
Ana Ortega, Estefanía Tarazón, Carolina Gil-Cayuela, María García-Manzanares, Luis Martínez-Dolz, Francisca Lago, José Ramón González-Juanatey, Juan Cinca, Esther Jorge, Manuel Portolés, Esther Roselló-Lletí, Miguel Rivera
Alterations in myocardial structure and reduced cardiomyocyte adhesions have been previously described in dilated cardiomyopathy (DCM). We studied the transcriptome of cell adhesion molecules in these patients and their relationships with left ventricular (LV) function decay. We also visualized the intercalated disc (ID) structure and organization. The transcriptomic profile of 23 explanted LV samples was analyzed using RNA-sequencing (13 DCM, 10 control [CNT]), focusing on cell adhesion genes. Electron microscopy analysis to visualize ID structural differences and immunohistochemistry experiments of ID proteins was also performed...
2017: PloS One
Nancy Martínez-Montiel, Laura Morales-Lara, Julio M Hernández-Pérez, Rebeca D Martínez-Contreras
The molecular mechanisms regulating the accuracy of gene expression are still not fully understood. Among these mechanisms, Nonsense-mediated Decay (NMD) is a quality control process that detects post-transcriptionally abnormal transcripts and leads them to degradation. The UPF1 protein lays at the heart of NMD as shown by several structural and functional features reported for this factor mainly for Homo sapiens and Saccharomyces cerevisiae. This process is highly conserved in eukaryotes but functional diversity can be observed in various species...
2016: PloS One
Jessica L Horsham, Clarissa Ganda, Felicity C Kalinowski, Rikki A M Brown, Michael R Epis, Peter J Leedman
MicroRNAs (miRNAs) are a family of short, non-coding RNA molecules (∼22nt) involved in post-transcriptional control of gene expression. They act via base-pairing with mRNA transcripts that harbour target sequences, resulting in accelerated mRNA decay and/or translational attenuation. Given miRNAs mediate the expression of molecules involved in many aspects of normal cell development and functioning, it is not surprising that aberrant miRNA expression is closely associated with many human diseases. Their pivotal role in driving a range of normal cellular physiology as well as pathological processes has established miRNAs as potential therapeutics, as well as potential diagnostic and prognostic tools in human health...
December 2015: International Journal of Biochemistry & Cell Biology
Junwei Nie, Mingyang Jiang, Xiaotian Zhang, Hao Tang, Hengwei Jin, Xinyi Huang, Baiyin Yuan, Chenxi Zhang, Janice Ching Lai, Yoshikuni Nagamine, Dejing Pan, Wengong Wang, Zhongzhou Yang
RNA G-quadruplexes (G4s) play important roles in RNA biology. However, the function and regulation of mRNA G-quadruplexes in embryonic development remain elusive. Previously, we identified RHAU (DHX36, G4R1) as an RNA helicase that resolves mRNA G-quadruplexes. Here, we find that cardiac deletion of Rhau leads to heart defects and embryonic lethality in mice. Gene expression profiling identified Nkx2-5 mRNA as a target of RHAU that associates with its 5' and 3' UTRs and modulates its stability and translation...
October 27, 2015: Cell Reports
Sudhish Mishra, Vitaliy Reznikov, Victor A Maltsev, Nidas A Undrovinas, Hani N Sabbah, Albertas Undrovinas
KEY POINTS: Late Na(+) current (INaL) contributes to action potential remodelling and Ca(2+)/Na(+) changes in heart failure. The molecular identity of INaL remains unclear. The contributions of different Na(+) channel isoforms, apart from the cardiac isoform, remain unknown. We discovered and characterized a substantial contribution of neuronal isoform Nav1.1 to INaL. This new component is physiologically relevant to the control of action potential shape and duration, as well as to cell Ca(2+) dynamics, especially in heart failure...
March 15, 2015: Journal of Physiology
Andrea Dal Mas, Malgorzata Ewa Rogalska, Erica Bussani, Franco Pagani
Exon-specific U1 snRNAs (ExSpe U1s) are modified U1 snRNAs that interact with intronic sequences downstream of the 5' splice site (ss) by complementarity. This process restores exon skipping caused by different types of mutation. We have investigated the molecular mechanism and activity of these molecules in spinal muscular atrophy (SMA), a genetic neuromuscular disease where a silent exonic transition on the survival motor neuron 2 (SMN2) leads to exon 7 (E7) skipping. By using different cellular models, we show that a single chromosome-integrated copy of ExSpe U1 induced a significant correction of endogenous SMN2 E7 splicing and resulted in the restoration of the corresponding SMN protein levels...
January 8, 2015: American Journal of Human Genetics
Rebecca Lee, Bin Xu, J Eduardo Rame, Leanne E Felkin, Paul Barton, Daniel L Dries
BACKGROUND: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood...
December 2014: Journal of the American Heart Association
Sudhish Mishra, Vitaliy Reznikov, Victor A Maltsev, Nidas A Undrovinas, Hani N Sabbah, Albertas Undrovinas
Late Na(+) current (INaL) contributes to action potential (AP) duration and Ca(2+) handling in cardiac cells. Augmented INaL was implicated in delayed repolarization and impaired Ca(2+) handling in heart failure (HF). We tested if Na(+) channel (Nav's) neuronal isoforms contribute to INaL and Ca(2+) cycling defects in HF in 17 dogs with HF achieved via sequential coronary artery embolizations. Six normal dogs served as control. Transient Na(+) current (INaT) and INaL in left ventricular cardiomyocytes (VCMs) were recorded by patch-clamp while Ca(2+) dynamics was monitored using fluo-4...
October 17, 2014: Journal of Physiology
Karni S Moshal, Zhe Zhang, Karim Roder, Tae Yun Kim, Leroy Cooper, Bogdan Patedakis Litvinov, Yichun Lu, Vishal Reddy, Dmitry Terentyev, Bum-Rak Choi, Gideon Koren
We recently showed that progesterone treatment abolished arrhythmias and sudden cardiac death in a transgenic rabbit model of long QT syndrome type 2 (LQT2). Moreover, levels of cardiac sarco(endo)plasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) were upregulated in LQT2 heart extracts. We hypothesized that progesterone treatment upregulated SERCA2a expression, thereby reducing Ca(2+)-dependent arrhythmias in LQT2 rabbits. We therefore investigated the effect of progesterone on SERCA2a regulation in isolated cardiomyocytes...
December 1, 2014: American Journal of Physiology. Cell Physiology
Leena Kaikkonen, Johanna Magga, Veli-Pekka Ronkainen, Elina Koivisto, Ábel Perjes, J Kurt Chuprun, Leif Erik Vinge, Teemu Kilpiö, Jani Aro, Johanna Ulvila, Tarja Alakoski, James A Bibb, Istvan Szokodi, Walter J Koch, Heikki Ruskoaho, Risto Kerkelä
cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38...
February 2014: Journal of Molecular and Cellular Cardiology
Shigeru Suzuki, Atsushi Nakao, Ashoor R Sarhat, Akiko Furuya, Kumihiro Matsuo, Yusuke Tanahashi, Hiroki Kajino, Hiroshi Azuma
Recently, GATA6 heterozygous loss-of-function mutations were reported to cause pancreatic agenesis and congenital heart defects (PACHD [OMIM:600001]). However, the molecular mechanisms resulting from premature termination codons have not been examined in this disorder. The objective of this study was to perform a genetic analysis of a patient with PACHD. A female patient presented with ventricular septal defect, patent ductus arteriosus, and congenital diaphragmatic hernia at birth. Permanent neonatal diabetes mellitus and pancreatic exocrine deficiency due to pancreatic agenesis was diagnosed at 1 month of age...
February 2014: American Journal of Medical Genetics. Part A
Gaetan Lesca, Marie-Pierre Moizard, Gerald Bussy, Dominique Boggio, Hao Hu, Stefan A Haas, Hans-Hilger Ropers, Vera M Kalscheuer, Vincent Des Portes, Audrey Labalme, Damien Sanlaville, Patrick Edery, Martine Raynaud, James Lespinasse
FG syndrome, Lujan syndrome, and Ohdo syndrome, the Maat-Kievit-Brunner type, have been described as distinct syndromes with overlapping non-specific features and different missense mutations of the MED12 gene have been reported in all of them. We report a family including 10 males and 1 female affected with profound non-specific intellectual disability (ID) which was linked to a 30-cM region extending from Xp11.21 (ALAS2) to Xq22.3 (COL4A5). Parallel sequencing of all X-chromosome exons identified a frameshift mutation (c...
December 2013: American Journal of Medical Genetics. Part A
Pietro Spitali, Janneke C van den Bergen, Ingrid E C Verhaart, Beatrijs Wokke, Anneke A M Janson, Rani van den Eijnde, Johan T den Dunnen, Jeroen F J Laros, Jan J G M Verschuuren, Peter A C 't Hoen, Annemieke Aartsma-Rus
Duchenne and Becker muscular dystrophies are caused by out-of-frame and in-frame mutations, respectively, in the dystrophin encoding DMD gene. Molecular therapies targeting the precursor-mRNA are in clinical trials and show promising results. These approaches will depend on the stability and expression levels of dystrophin mRNA in skeletal muscles and heart. We report that the DMD gene is more highly expressed in heart than in skeletal muscles, in mice and humans. The transcript mutated in the mdx mouse model shows a 5' to 3' imbalance compared with that of its wild-type counterpart and reading frame restoration via antisense-mediated exon skipping does not correct this event...
December 2013: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Eonyoung Park, Lynne E Maquat
Staufen1 (STAU1)-mediated mRNA decay (SMD) is an mRNA degradation process in mammalian cells that is mediated by the binding of STAU1 to a STAU1-binding site (SBS) within the 3'-untranslated region (3'-UTR) of target mRNAs. During SMD, STAU1, a double-stranded (ds) RNA-binding protein, recognizes dsRNA structures formed either by intramolecular base pairing of 3'-UTR sequences or by intermolecular base pairing of 3'-UTR sequences with a long-noncoding RNA (lncRNA) via partially complementary Alu elements. Recently, STAU2, a paralog of STAU1, has also been reported to mediate SMD...
July 2013: Wiley Interdisciplinary Reviews. RNA
Machender R Kandadi, Nan Hu, Jun Ren
This study was designed to evaluate the role of ULK1 in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. Wild-type and AMPK knockout mice were challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial function was evaluated using echocardiography and edge-detection. Western blot analysis was employed to evaluate the levels of AMPK, Raptor, mTOR, the AMPK downstream signal ULK1 and autophagy markers Beclin-1 and LC3-II. siRNA was used to knockdown ULK1 in H9C2 myoblasts...
2013: Current Pharmaceutical Design
A Tagariello, C Breuer, Y Birkner, S Schmidt, A M Koch, R Cesnjevar, A Ruffer, S Dittrich, H Schneider, A Winterpacht, H Sticht, J Dotsch, O Toka
In patients with congenital heart defects, chromosomal anomalies are 100 times more frequent than in control subjects. Coarctation of the aorta can be detected in 15-20% of patients with Ullrich-Turner syndrome. By extensively reviewing literature involving breakpoint analysis of gonosomal deletions in Ullrich- Turner syndrome patients with and without coarctation of the aorta, we identified several gonosomal homolgous gene pairs of interest. Four of these homologous gene pairs were investigated by standard DNA sequencing in a cohort of 83 patients with non-syndromic coarctation of the aorta...
February 2012: Current Molecular Medicine
Twishasri Dasgupta, Andrea N Ladd
RNA processing is important for generating protein diversity and modulating levels of protein expression. The CUG-BP, Elav-like family (CELF) of RNA-binding proteins regulate several steps of RNA processing in the nucleus and cytoplasm, including pre-mRNA alternative splicing, C to U RNA editing, deadenylation, mRNA decay, and translation. In vivo, CELF proteins have been shown to play roles in gametogenesis and early embryonic development, heart and skeletal muscle function, and neurosynaptic transmission...
January 2012: Wiley Interdisciplinary Reviews. RNA
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