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Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.
Ma D, Tu C, Sheng Q, Yang Y, Kan Z, Guo Y, Shyr Y, Scott IC, Lou X
(2018) J Proteome Res 17: 1300-1308
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Fish Proteins, Gene Ontology, Heart Injuries, Heart Ventricles, Metabolic Networks and Pathways, Molecular Sequence Annotation, Myocardium, Proteomics, Real-Time Polymerase Chain Reaction, Regeneration, Spectrometry, Mass, Electrospray Ionization, Tumor Suppressor Protein p53, Zebrafish
Show Abstract · Added April 3, 2018
Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.
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15 MeSH Terms
Loss of αB-crystallin function in zebrafish reveals critical roles in the development of the lens and stress resistance of the heart.
Mishra S, Wu SY, Fuller AW, Wang Z, Rose KL, Schey KL, Mchaourab HS
(2018) J Biol Chem 293: 740-753
MeSH Terms: Animals, Cardiomyopathies, Edema, Glucocorticoids, Image Processing, Computer-Assisted, Lens, Crystalline, Molecular Chaperones, Mutation, Myocardium, Pericardium, Phenotype, Receptors, Glucocorticoid, Signal Transduction, Stress, Physiological, Transgenes, Zebrafish, alpha-Crystallin A Chain, alpha-Crystallin B Chain
Show Abstract · Added April 3, 2018
Genetic mutations in the human small heat shock protein αB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity , the functions of αB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of αB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two αB-crystallin genes, α and α We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in α than α mutants. This finding is in contrast with the lack of a phenotype previously reported in αB-crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for αB-crystallin in providing stress tolerance to the heart. The αB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of αB-crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of αB-crystallin in the maintenance of lens transparency.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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18 MeSH Terms
Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy.
Litt MJ, Okoye GD, Lark D, Cakir I, Moore C, Barber MC, Atkinson J, Fessel J, Moslehi J, Cone RD
(2017) Elife 6:
MeSH Terms: Adenosine Diphosphate, Animals, Cardiomyopathy, Dilated, Cell Respiration, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Myocardium, Myocytes, Cardiac, Reactive Oxygen Species, Receptor, Melanocortin, Type 4
Show Abstract · Added December 2, 2017
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production - a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.
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11 MeSH Terms
Cardiac repair in a mouse model of acute myocardial infarction with trophoblast stem cells.
Li G, Chen J, Zhang X, He G, Tan W, Wu H, Li R, Chen Y, Gu R, Xie J, Xu B
(2017) Sci Rep 7: 44376
MeSH Terms: Animals, Cardiac Surgical Procedures, Cell Differentiation, Disease Models, Animal, Humans, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Myocardial Infarction, Myocardium, Myocytes, Cardiac, Trophoblasts
Show Abstract · Added September 11, 2017
Various stem cells have been explored for the purpose of cardiac repair. However, any individual stem cell population has not been considered as the ideal source. Recently, trophoblast stem cells (TSCs), a newly described stem cell type, have demonstrated extensive plasticity. The present study evaluated the therapeutic effect of TSCs transplantation for heart regeneration in a mouse model of myocardial infarction (MI) and made a direct comparison with the most commonly used mesenchymal stem cells (MSCs). Transplantation of TSCs and MSCs led to a remarkably improved cardiac function in contrast with the PBS control, but only the TSCs exhibited the potential of differentiation into cardiomyocytes in vivo. In addition, a significantly high proliferation level of both transplanted stem cells and resident cardiomyocytes was observed in the TSCs group. These findings primary revealed the therapeutic potential of TSCs in transplantation therapy for MI.
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12 MeSH Terms
Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy.
Zhang B, Novitskaya T, Wheeler DG, Xu Z, Chepurko E, Huttinger R, He H, Varadharaj S, Zweier JL, Song Y, Xu M, Harrell FE, Su YR, Absi T, Kohr MJ, Ziolo MT, Roden DM, Shaffer CM, Galindo CL, Wells QS, Gumina RJ
(2017) Circ Heart Fail 10:
MeSH Terms: Adult, Animals, Calcium Channels, L-Type, Calcium Signaling, Calcium-Binding Proteins, Cardiomyopathies, Case-Control Studies, Disease Models, Animal, Female, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, Oxidative Stress, Phenotype, Potassium Channels, Inwardly Rectifying, Reactive Nitrogen Species, Reactive Oxygen Species, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tyrosine, Ventricular Dysfunction, Left, Ventricular Function, Left, Ventricular Pressure
Show Abstract · Added April 6, 2017
BACKGROUND - Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.
METHODS AND RESULTS - RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.
CONCLUSIONS - expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
© 2017 American Heart Association, Inc.
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28 MeSH Terms
Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2.
Bylund JB, Trinh LT, Awgulewitsch CP, Paik DT, Jetter C, Jha R, Zhang J, Nolan K, Xu C, Thompson TB, Kamp TJ, Hatzopoulos AK
(2017) Stem Cells Dev 26: 678-693
MeSH Terms: Bone Morphogenetic Proteins, Cell Differentiation, Cell Line, Cell Proliferation, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Intercellular Signaling Peptides and Proteins, Myocardium, Myocytes, Cardiac, Organogenesis, Signal Transduction, Stem Cells
Show Abstract · Added September 6, 2017
Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells (CPCs), but how the two processes are synchronized is not well understood. Here, we show that the secreted Bone Morphogenetic Protein (BMP) antagonist GREMLIN 2 (GREM2) is induced in CPCs shortly after cardiac mesoderm specification during differentiation of human pluripotent stem cells. GREM2 expression follows cardiac lineage differentiation independently of the differentiation method used, or the origin of the pluripotent stem cells, suggesting that GREM2 is linked to cardiogenesis. Addition of GREM2 protein strongly increases cardiomyocyte output compared to established procardiogenic differentiation methods. Our data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of CPCs. However, canonical BMP signaling inhibition alone is not sufficient to induce cardiac differentiation, which depends on subsequent JNK pathway activation specifically by GREM2. These findings may have broader implications in the design of approaches to orchestrate growth and differentiation of pluripotent stem cell-derived lineages that depend on precise regulation of BMP signaling.
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15 MeSH Terms
Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region.
Datta K, Basak T, Varshney S, Sengupta S, Sarkar S
(2017) J Proteomics 152: 283-299
MeSH Terms: Cytoskeletal Proteins, Desmin, Heart Failure, Humans, Myocardial Infarction, Myocardium, Oxidative Stress, Proteomics, Spatio-Temporal Analysis, Ventricular Remodeling
Show Abstract · Added November 3, 2017
Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%-45% of patients developing heart failure, in a period of 5-25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling.
SIGNIFICANCE - Oxidative stress is the major driving force for cardiac damage during myocardial infarction. However, the impact of oxidative stress on the process of post MI remodeling in conducting the heart towards functional failure has not been well explored. In this study, a spatial and temporal approach was taken to elaborate the major proteins and cellular processes involved in post MI remodeling. Based on level/ intensity of ROS, spatially, infarct and noninfarct zones were chosen for analysis while on the temporal scale, early (30days) and late time points (120days) post MI were included in the study. This design enabled us to delineate the differential protein expression on a spectrum of maximum oxidative stress at infarct zone during MI to minimum oxidative stress at noninfarct zone during late time point post MI. The proteome profiles for each of the study groups when comparatively analysed gave a holistic idea about the dominant cellular processes involved in post MI remodeling such as cardiac metabolism, both for short term and long term remodeling as well as unique processes such as Desmin mediated cytoskeletal remodeling of the infarcted myocardium that are involved in the compromise of cardiac function.
Copyright © 2016 Elsevier B.V. All rights reserved.
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10 MeSH Terms
Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart.
Stroud DM, Yang T, Bersell K, Kryshtal DO, Nagao S, Shaffer C, Short L, Hall L, Atack TC, Zhang W, Knollmann BC, Baudenbacher F, Roden DM
(2016) J Am Heart Assoc 5:
MeSH Terms: Action Potentials, Animals, Electrocardiography, Heart, Heart Ventricles, Isolated Heart Preparation, Mice, Mice, Knockout, Myocardium, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 3, 2017
BACKGROUND - Genome-wide association studies have implicated variants in SCN10A, which encodes Nav1.8, as modulators of cardiac conduction. Follow-up work has indicated the SCN10A sequence includes an intronic enhancer for SCN5A. Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this, we use homozygous knockout mice (Scn10a) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact.
METHODS AND RESULTS - We previously reported that pharmacologic blockade of Nav1.8 in wild-type animals blunts action potential prolongation by ATX-II at slow drive rates (≤1 Hz). Here we present evidence of the same blunting in Scn10a compared to wild-type ventricular myocytes, supporting the conclusion that Nav1.8 contributes to late sodium current at slow rates. In contrast to earlier studies, we found no differences in electrocardiographic parameters between genotypes. Low-dose ATX-II exposure in lightly anesthetized animals and Langendorff-perfused hearts prolonged QTc and generated arrhythmias to the same extent in wild-type and Scn10a. RNA sequencing failed to identify full-length Scn10a transcripts in wild-type or knockout isolated ventricular myocytes. However, loss of late current in Scn10a myocytes was replicated independently in a blinded set of experiments.
CONCLUSIONS - While Scn10a transcripts are not detectible in ventricular cardiomyocytes, gene deletion results in reproducible loss of late sodium current under extreme experimental conditions. However, there are no identifiable consequences of this Scn10a deletion in the intact mouse heart at usual rates. These findings argue that common variants in SCN10A that affect ventricular conduction do so by modulating SCN5A.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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14 MeSH Terms
Fulminant Myocarditis with Combination Immune Checkpoint Blockade.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA, Anders RA, Sosman JA, Moslehi JJ
(2016) N Engl J Med 375: 1749-1755
MeSH Terms: Aged, Antibodies, Monoclonal, Arrhythmias, Cardiac, Electrocardiography, Fatal Outcome, Female, Glucocorticoids, Heart Block, Humans, Immunotherapy, Ipilimumab, Male, Melanoma, Middle Aged, Myocarditis, Myocardium, Myositis, Nivolumab
Show Abstract · Added March 26, 2017
Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).
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18 MeSH Terms
Transcription factor ETV1 is essential for rapid conduction in the heart.
Shekhar A, Lin X, Liu FY, Zhang J, Mo H, Bastarache L, Denny JC, Cox NJ, Delmar M, Roden DM, Fishman GI, Park DS
(2016) J Clin Invest 126: 4444-4459
MeSH Terms: Animals, DNA-Binding Proteins, Heart Atria, Heart Conduction System, Heart Ventricles, Homeobox Protein Nkx-2.5, Humans, Mice, Mice, Transgenic, Myocardium, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Transcription Factors
Show Abstract · Added March 14, 2018
Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.
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13 MeSH Terms