24 results on '"Dudley Jr, Samuel C."'
Search Results
2. RBM25/LUC7L3 Function in Cardiac Sodium Channel Splicing Regulation of Human Heart Failure.
- Author
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Ge Gao and Dudley Jr., Samuel C.
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HEART failure , *GENE expression , *MESSENGER RNA , *RNA interference , *SODIUM channels , *HYPOXEMIA , *ANGIOTENSINS - Abstract
Alternative splicing is a posttranscriptional mechanism that can substan-tially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure (HF), we found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF. Our results show that angiotensin II and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na+ current. These observations may shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na+ channel blocking anti-arrhythmic drug complications. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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3. Tandem Promoters and Developmentally Regulated 5'- and 3'-mRNA Untranslated Regions of the Mouse Scn5a Cardiac Sodium Channel.
- Author
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Shang, Lijuan L. and Dudley Jr., Samuel C.
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MESSENGER RNA , *GENETIC polymorphisms , *SODIUM channels , *ARRHYTHMIA , *HEART diseases , *MUSCLE cells , *CELL culture , *CELL lines - Abstract
The SCN5A gene encodes a voltage-sensitive sodium channel expressed in cardiac and skeletal muscle. Coding region mutations cause cardiac sudden death syndromes and conduction system failure. Polymorphisms in the 5'-sequence adjacent to the SCN5A gene have been linked to cardiac arrhythmias. We identified three alternative 5'-splice variants (1A, 1B, and 1C) of the untranslated exon 1 and two 3'-variants in the murine Scn5a mRNA. Two of the exon 1 isoforms (1B and 1C) were novel when compared with the published human and rat SCN5A sequences. Quantitative real time PCR results showed that the abundance of the isoforms varied during cardiac development. The 1A, 1B, and 1C mRNA splice variants increased 7.8 ± 1.7-fold (E1A), 6.0 ± 1.0-fold (E1B), and 20.6 ± 3.7-fold (E1C) from fetal to adult heart, respectively. Promoter deletion and luciferase reporter gene analysis using cardiac and skeletal muscle cell lines demonstrated a pattern of distinct cardiac-specific enhancer elements associated with exons 1A and 1C. In the case of exon 1C, the enhancer element appeared to be within the exon. A 5'-repressor preceded each cardiac enhancer element. We concluded that the murine Na+ channel has both 5'- and 3'-untranslated region mRNA variants that are developmentally regulated and that the promoter region contains two distinct cardiac-specific enhancer regions. The presence of homologous human splicing suggests that that these regions may be fruitful new areas of study in understanding cardiac sodium channel regulation and the genetic susceptibility to sudden death. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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4. Mu Conotoxin GIIIA Interactions with the Voltage-Gated Na [sup +] Channel Predict a Clockwise Arrangement of the Domains.
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Dudley Jr., Samuel C. and Chang, Nancy
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SODIUM channels , *ELECTROPHYSIOLOGY - Abstract
Presents information on a study which probed the rat adult skeletal muscle sodium+ channel outer vestibule and selectivity filter using mu conotoxin GIIIA. Methodology of the study; Results and discussion on the study.
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- 2000
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5. Cardiac Development Long Non-Coding RNA (CARDEL) Is Activated during Human Heart Development and Contributes to Cardiac Specification and Homeostasis.
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Pereira, Isabela T., Gomes-Júnior, Rubens, Hansel-Frose, Aruana, França, Rhaíza S. V., Liu, Man, Soliman, Hossam A. N., Chan, Sunny S. K., Dudley Jr., Samuel C., Kyba, Michael, and Dallagiovanna, Bruno
- Abstract
Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. Unitary conductance of Na+ channel isoforms in cardiac and NB2a neuroblastoma cells.
- Author
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Baumgarten, Clive M. and Dudley Jr., Samuel C.
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SODIUM channels - Abstract
Determines unitary conductances of native Na+ channel isoforms (alphaNa) under a variety of conditions. Basis of a linear least-squares fit; Comparison of nerve and cardiac Na+ channels; Mean open time; Unitary current-voltage relationships for neuroblastoma.
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- 1995
7. New Diagnostic and Therapeutic Possibilities For Diastolic Heart Failure.
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JEONG, EUY-MYOUNG and DUDLEY JR., SAMUEL C.
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HEART failure , *OXIDATIVE stress , *DISEASE incidence , *DISEASE prevalence , *HEART failure treatment , *DIAGNOSIS - Abstract
Despite the fact that up to half of all heart failure occurs in patients without evidence of systolic cardiac dysfunction, there are no universally accepted diagnostic markers and no approved therapies for heart failure with preserved ejection fraction (HFpEF). HFpEF, otherwise known as diastolic heart failure, has nearly the same grim prognosis as systolic heart failure, and diastolic heart failure is increasing in incidence and prevalence. Major trials have shown that many of the treatments that are salutary in systolic heart failure have no beneficial effects in diastolic heart failure, suggesting different underlying mechanisms for these two disorders. Even criteria for diagnosis of HFpEF are still debated, and there is still no gold standard marker to detect diastolic dysfunction. Here, we will review some promising new insights into the pathogenesis of diastolic dysfunction that may lead to new diagnostic and therapeutic tools. [ABSTRACT FROM AUTHOR]
- Published
- 2014
8. Oxidative stress and atrial fibrillation: finding a missing piece to the puzzle.
- Author
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Yang, Kai-Chien, Dudley Jr, Samuel C, and Dudley, Samuel C Jr
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- 2013
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9. Oxidative Stress and Atrial Fibrillation.
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Kai-Chien Yang and Dudley Jr., Samuel C.
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ATRIAL fibrillation , *OXIDATIVE stress , *CALCIUM ions , *PROTEIN kinases , *ANGIOTENSIN I - Abstract
The article comments on a study by A. Purohit and colleagues which examined the role of oxidized Ca2+ and calmodulin-dependent protein kinase II (ox-CaMKII) in modulating atrial fibrillation (AF) induced by angiotensin II (AngII). Results of the study suggest a mechanistic link between AF and oxidative stress. An increased ox-CaMKII expression was found in the atrial tissue of AF patients.
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- 2013
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10. Ion channelopathies: a tapped-out mine?
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Dudley Jr., Samuel C.
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ION channels , *DNA , *GENETIC mutation , *VENTRICULAR tachycardia , *BRUGADA syndrome , *CALCIUM - Published
- 2011
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11. Cardiac sodium channel mutations: why so many phenotypes?
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Man Liu, Kai-Chien Yang, and Dudley Jr, Samuel C.
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SODIUM channels , *ATRIAL fibrillation , *BRUGADA syndrome , *CARDIOMYOPATHIES , *GENETIC mutation , *RNA - Abstract
Mutations of the cardiac sodium channel (Nav 1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype-phenotype correlations difficult. In this Perspectives article, we propose th at phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype-phenotype correlations and lead to new therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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12. The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: A potent sodium-channel blocker.
- Author
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Votsu-Yamashita, Mari, Kim, Yong H., Dudley Jr., Samuel C., Choudhary, Gaurav, Pfahnl, Arnold, Oshima, Yasukatsu, and Daly, John W.
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ATELOPUS , *GUANIDINE , *BUFONIDAE , *TETRODOTOXIN , *ANURA , *SODIUM channels , *GUANIDINES - Abstract
Bufonid anurans of the genus Atelopus contain both steroidal bufadienolides and various guanidinium alkaloids of the tetrodotoxin class. The former inhibit sodium-potassium ATPases, whereas the latter block voltage-dependent sodium channels. The structure of one guanidinium alkaloid, zetekitoxin AB, has remained a mystery for over 30 years. The structure of this alkaloid now has been investigated with a sample of ≈0.3 mg, purified from extracts obtained decades ago from the Panamanian golden frog Atelopus zeteki. Detailed NMR and mass spectral analyses have provided the structure and relative stereochemistry of zetekitoxin AB and have revealed that it is an analog of saxitoxin. The proposed structure is characterized by richness of heteroatoms (C16H25N8O12S) and contains a unique 1,2-oxazolidine ring-fused lactam, a sulfate ester, and an N-hydroxycarbamate moiety. Zetekitoxin AB proved to be an extremely potent blocker of voltage-dependent sodium channels expressed in Xenopus oocytes. The IC50 values were 280 pM for human heart channels, 6.1 pM for rat brain IIa channels, and 65 pM for rat skeletal muscle channels, thus being roughly 580-, 160-, and 63-fold more potent at these channels than saxitoxin. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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13. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction.
- Author
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Man Liu, Hong Liu, Parthiban, Preethy, Gyeoung-Jin Kang, Guangbin Shi, Feng Feng, Anyu Zhou, Lianzhi Gu, Karnopp, Courtney, Tolkacheva, Elena G., and Dudley Jr., Samuel C.
- Abstract
Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase–like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmia risk after myocardial infarct (MI). MI induced in mice by coronary artery ligation resulted in reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves on the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK KO reduced electrical remodeling in response to MI, with shortened QTc intervals, fewer VT episodes, and higher survival rates. Pharmacological PERK inhibition had similar effects. In conclusion, we found that activated PERK during MI contributed to arrhythmia risk by the downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmia risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmia mechanism and that maintenance of ion channel levels is antiarrhythmic. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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14. The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2.
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Turan, Nilüfer N., Moshal, Karni S., Roder, Karim, Baggett, Brett C., Kabakov, Anatoli Y., Dhakal, Saroj, Ryota Teramoto, Yi-Eng Chiang, David, Mingwang Zhong, An Xie, Yichun Lu, Dudley Jr, Samuel C., MacRae, Calum A., Karma, Alain, and Koren, Gideon
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SODIUM channels , *UBIQUITIN , *UBIQUITIN ligases , *TUMOR necrosis factors , *UBIQUITINATION , *CARDIAC patients - Abstract
The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide- induced tumor necrosis factor-a factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed inHEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression downregulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressedNEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation ofNEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca21 and Na1 homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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15. SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR.
- Author
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Tae Yun Kim, Terentyeva, Radmila, Roder, Karim H. F., Weiyan Li, Man Liu, Greener, Ian, Hamilton, Shanna, Polina, Iuliia, Murphy, Kevin R., Clements, Richard T., Dudley Jr, Samuel C., Koren, Gideon, Bum-Rak Choi, and Terentyev, Dmitry
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PHYSIOLOGICAL effects of potassium channels , *RYANODINE receptors , *OXYGEN in the body , *CARDIAC hypertrophy , *CALCIUM channels regulation , *ARRHYTHMIA , *HYPERTROPHIC cardiomyopathy - Abstract
Aims: Plasmamembrane small conductance Ca2+-activated K+(SK) channels were implicated in ventricular arrhythmias in infarcted and failing hearts. Recently, SK channels were detected in the inner mitochondria membrane (IMM) (mSK), and their activation protected from acute ischaemia-reperfusion injury by reducing intracellular levels of reactive oxygen species (ROS). We hypothesized that mSK play an important role in regulating mitochondrial function in chronic cardiac diseases. We investigated the role of mSK channels in Ca2+-dependent ventricular arrhythmia using rat model of cardiac hypertrophy induced by banding of the ascending aorta thoracic aortic banding (TAB). Methods and results: Dual Ca2+and membrane potential optical mapping of whole hearts derived from TAB rats revealed that membrane-permeable SK enhancer NS309 (2 μM) improved aberrant Ca2þhomeostasis and abolished VT/VF induced by b-adrenergic stimulation. Using whole cell patch-clamp and confocal Ca2+imaging of cardiomyocytes derived from TAB hearts (TCMs) we found that membrane-permeable SK enhancers NS309 and CyPPA (10 μM) attenuated frequency of spontaneous Ca2+waves and delayed afterdepolarizations. Furthermore, mSK inhibition enhanced (UCL-1684, 1 μM); while activation reduced mitochondrial ROS production in TCMs measured with MitoSOX. Protein oxidation assays demonstrated that increased oxidation of ryanodine receptors (RyRs) in TCMs was reversed by SK enhancers. Experiments in permeabilized TCMs showed that SK enhancers restored SR Ca2+content, suggestive of substantial improvement in RyR function. Conclusion These data suggest that enhancement of mSK channels in hypertrophic rat hearts protects from Ca2+-dependent arrhythmia and suggest that the protection is mediated via decreased mitochondrial ROS and subsequent decreased oxidation of reactive cysteines in RyR, which ultimately leads to stabilization of RyR-mediated Ca2+release. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Nitroglycerin Tolerance in Caveolin-1 Deficient Mice.
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Mao, Mao, Varadarajan, Sudhahar, Fukai, Tohru, Bakhshi, Farnaz R., Chernaya, Olga, Dudley Jr., Samuel C., Minshall, Richard D., and Bonini, Marcelo G.
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CAVEOLINS , *PROTEIN deficiency , *DRUG tolerance , *LABORATORY mice , *VASODILATORS , *NITRIC-oxide synthases ,THERAPEUTIC use of nitroglycerin - Abstract
Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48–72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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17. DERMATITIS HERPETIFORMIS BODIES AND AUTOANTIBODIES TO NONCUTANEOUS ORGANS AND MITOCHONDRIA IN DERMATITIS HERPETIFORMIS.
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Abreu Velez, Ana Maria, Hong Yi, Girard, Julia Griffin, Zhe Jiao, Ramírez, Mauricio Duque, Arias, Luis F., Smoller, Bruce B., Dudley Jr., Samuel C., and Howard, Michael S.
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DERMATITIS herpetiformis , *AUTOANTIBODIES , *IMMUNOGLOBULIN A , *VELOCARDIOFACIAL syndrome , *AMALGAMATION - Abstract
Introduction: The precise nature of the previously described dermatitis herpetiformis bodies remains unknown. Aims: Our study was conducted to investigate the nature of dermatitis herpetiformis bodies in the skin in 7 cases of dermatitis herpetiformis, and to search for the presence of autoantibodies in other organs. Methods: We utilized clinical, histopathologic, and immunologic methods to evaluate these patients. Results: Dermatitis herpetiformis bodies were found to be comprised of an amalgamation of immunoglobulins A and M, as well as molecules reactive with antibodies to armadillo repeat gene deleted in velo-cardio-facial syndrome, desmoplakins 1 and 2, and plakophilin 4. In addition, we found immunologic colocalization with selected autoantibodies associated with mitochondria in the skin, heart, kidney, and peripheral nerves. The dermatitis herpetiformis bodies did not demonstrate immunologic colocalization with tissue/epidermal transglutaminase. Conclusions: The complete biochemical nature of dermatitis herpetiformis bodies requires further characterization. Dermatitis herpetiformis bodies in these patients appear to be distinctly different than cytoid bodies. Further studies are required to determine if the antibodies to noncutaneous organs are pathogenic, and/or contribute to systemic morbility in dermatitis herpetiformis patients. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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18. Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure.
- Author
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Ge Gao, An Xie, Shu-Ching Huang, Anyu Zhou, Jianhua Zhang, Herman, Amanda M., Ghassemzadeh, Sassan, Euy-Myoung Jeong, Kasturirangan, Srinivasan, Raicu, Mihai, Sobieski II, Michael A., Bhat, Geetha, Tatooles, Antone, Benz Jr., Edward J., Kamp, Timothy J., and Dudley Jr., Samuel C.
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SODIUM channels , *HEART failure , *MESSENGER RNA , *ARRHYTHMIA ,HEART disease research - Abstract
Background—Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. Methods and Results—Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. Conclusions—Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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19. Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse.
- Author
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Reed, Alana L., Tanaka, Atsuko, Sorescu, Dan, Hong Liu, Euy-Myoung Jeong, Sturdy, Megan, Walp, Erik R., Dudley Jr., Samuel C., and Sutliff, Roy L.
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FIBROSIS , *LASER Doppler blood flowmetry , *HEMODYNAMICS , *COLLAGEN diseases , *GENE expression - Abstract
Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice (P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively (P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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20. Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43.
- Author
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Iravanian, Shahriar, Sovari, Ali A., Lardin, Harvey A., Hong Liu, Xiao, Hong D., Dolmatova, Elena, Zhe Jiao, Harris, Brett S., Witham, Emily A., Gourdie, Robert G., Duffy, Heather S., Bernstein, Kenneth E., and Dudley, Jr., Samuel C.
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ACE inhibitors , *TACHYCARDIA , *ANTIHYPERTENSIVE agents , *HEART diseases , *IMMUNOHISTOCHEMISTRY , *VENTRICULAR tachycardia - Abstract
Renin-angiotensin system (RAS) activation is associated with arrhythmias. We investigated the effects of RAS inhibition in cardiac-specific angiotensin-converting enzyme (ACE) overexpression ( ACE 8/8) mice, which exhibit proclivity to ventricular tachycardia (VT) and sudden death because of reduced connexin43 (Cx43). ACE 8/8 mice were treated with an ACE inhibitor (captopril) or an angiotensin receptor type-1 blocker (losartan). Subsequently, electrophysiological studies were performed, and the hearts were extracted for Cx43 quantification using immunoblotting, immunohistochemistry, fluorescent dye spread method, and sodium current quantification using whole cell patch clamping. VT was induced in 12.5% of captopril-treated ACE 8/8 and in 28.6% of losartan-treated mice compared to 87.5% of untreated mice ( P < 0.01). Losartan and captopril treatment increased total Cx43 2.4-fold ( P = 0.01) and the Cx43 phosphorylation ratio 2.3-fold ( P = 0.005). Treatment was associated with a recovery of gap junctional conductance. Survival in treated mice improved to 0.78 at 10 weeks (95% confidence interval 0.64 to 0.92), compared to the expected survival of less than 0.50. In a model of RAS activation, arrhythmic risk was correlated with reduced Cx43 amount and phosphorylation. RAS inhibition resulted in increased total and phosphorylated Cx43, decreased VT inducibility, and improved survival. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
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21. Statins Decrease Oxidative Stress and ICD Therapies.
- Author
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Bloom, Heather L., Shukrullah, Irfan, Veledar, Emir, Gutmann, Rebecca, London, Barry, and Dudley Jr, Samuel C.
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STATINS (Cardiovascular agents) , *OXIDATIVE stress , *ARRHYTHMIA , *DEFIBRILLATORS , *OXIDATION , *INTERLEUKINS , *MYOCARDIAL depressants , *REGRESSION analysis , *CARDIAC research , *PHYSIOLOGY - Abstract
Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation. Methods. 304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6). Results. Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29 ± 27 months. Use of statins correlated with lower ICD events (r = 0.12, P = .02). Subjects on statins had lower hsCRP (5.2 versus 6.3; P = .05) and DROM levels (373 versus 397; P = .03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor. Conclusion. ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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22. NF-κB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II.
- Author
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Shang, Lijuan L., Sanyal, Shamarendra, Pfahnl, Arnold E., Zhe Jiao, Allen, Jon, Hong Liu, and Dudley Jr., Samuel C.
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ION channels , *MUSCLE cells , *PHOTOSYNTHETIC oxygen evolution , *COLLOIDS , *CARDIAC arrest , *MESSENGER RNA , *ACTIVE biological transport - Abstract
Angiotensin II (ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na+ channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG II- mediated oxidative stress may modulate Na+ channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or H2O2 (10 μmol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na+ current, respectively (P ⩽ 0.01). By quantitative real-time RT-PCR, the cardiac Na+ channel (scn5a) mRNA abundance declined by 47.3% (P < 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/l ANG II. A similar change occurred with 20 μmol/l H2O2 (46.9%, P < 0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of ANG II could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-κB binding site prevented decreased activity in response to ANG II and H2O2. Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-κB bound to the scn5a promoter in response to ANG II and H2O2. Overexpression of the p50 subunit of NF-κB in H9c2 cells reduced scn5a mRNA (77.3%, P < 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of H2O2 resulting in NF-κB binding to the Na+ channel promoter. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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23. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation.
- Author
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Kasi, Vijaykumar S., Xiao,, Hong D., Shang, Lijuan L, Iravanian, Shahriar, Langberg, Jonathan, Witham, Emily A., Zhe Jiao, Gallego, Carlos J., Bernstein, Kenneth E., and Dudley, Jr., Samuel C.
- Subjects
- *
RENIN-angiotensin system , *SUDDEN death , *ANGIOTENSIN converting enzyme , *ELECTROPHYSIOLOGY , *HUMAN abnormalities - Abstract
Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na+ channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca2+ channel, Kv4.2 K+ channel α-subunit, and Cx45 mRNA abundances and the peak ventricular Na+ current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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24. Characterization and regulation of T-type Ca[sup 2+] channels in embryonic stem cell-derived cardiomyocytes.
- Author
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Ying Ming Zhang, Patrice G., Lijuan Shang, Patrice G., Hartzell, Criss, Narlow, Michael, Cribbs, Leanne, and Dudley Jr., Samuel C.
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CALCIUM channels , *HEART cells , *STEM cells , *GENE expression , *POLYMERASE chain reaction - Abstract
T-type Ca[sup 2+] channels may play a role in cardiac development. We studied the developmental regulation of the T-type currents (I[sub Ca,T]) in cardiomyocytes (CMs) derived from mouse embryonic stem cells (ESCs). I[sub Ca,T] was studied in isolated CMs by whole cell patch clamp. Subsequently, CMs were identified by the myosin light chain 2v-driven green fluorescent protein expression, and laser capture microdissection was used to isolate total RNA from groups of cells at various developmental time points. I[sub Ca,T] showed characteristics of Ca[sub v]3.1, such as resistance to Ni[sup 2+] block, and a transient increase during development, correlating with measures of spontaneous electrical activity. Real-time RT-PCR showed that Ca[sub v]3.1 mRNA abundance correlated (r² = 0.81) with I[sub Ca,T]. The mRNA copy number was low at 7+4 days (2 copies/cell), increased significantly by 7+10 days (27/cell; P < 0.01), peaked at 7+16 days (174/cell), and declined significantly at 7+27 days (25/cell). These data suggest that I[sub Ca,T] is developmentally regulated at the level of mRNA abundance and that this regulation parallels measures of pacemaker activity, suggesting that I[sub Ca,T] might play a role in the spontaneous contractions during CM development. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
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