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Publication Record


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
Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.
Hernandez W, Gamazon ER, Aquino-Michaels K, Smithberger E, O'Brien TJ, Harralson AF, Tuck M, Barbour A, Cavallari LH, Perera MA
(2017) J Thromb Haemost 15: 735-743
MeSH Terms: Adult, African Americans, Aged, Algorithms, Calcium-Binding Proteins, Cohort Studies, Cytochrome P-450 CYP2C9, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Genotype, Humans, Linkage Disequilibrium, Liver, Male, Middle Aged, Pharmacogenetics, Precision Medicine, Quantitative Trait Loci, Thromboembolism, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added April 13, 2017
Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation.
SUMMARY - Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.
© 2017 International Society on Thrombosis and Haemostasis.
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23 MeSH Terms
Genetic determinants of variability in warfarin response after the dose-titration phase.
Iwuchukwu OF, Ramirez AH, Shi Y, Bowton EA, Kawai VK, Schildcrout JS, Roden DM, Denny JC, Stein CM
(2016) Pharmacogenet Genomics 26: 510-516
MeSH Terms: Adult, African Americans, Aged, Aged, 80 and over, Anticoagulants, Calcium-Binding Proteins, Carbon-Carbon Ligases, Cytochrome P-450 CYP2C9, Cytochrome P450 Family 4, Epoxide Hydrolases, European Continental Ancestry Group, Female, Humans, International Normalized Ratio, Male, Middle Aged, Pharmacogenomic Variants, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 14, 2018
OBJECTIVES - Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known.
METHODS - Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans.
RESULTS - One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR.
CONCLUSION - The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
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19 MeSH Terms
Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress.
Hines-Beard J, Bond WS, Backstrom JR, Rex TS
(2016) J Neuroinflammation 13: 39
MeSH Terms: Animals, Calcium-Binding Proteins, Cholera Toxin, Cytokines, Dependovirus, Disease Models, Animal, Erythropoietin, Evoked Potentials, Visual, Fluorescein Angiography, Gene Expression Regulation, Genetic Therapy, Glaucoma, Ki-67 Antigen, Mice, Mice, Inbred DBA, Microfilament Proteins, Microglia, Oxidative Stress, Photic Stimulation, Retina, Transduction, Genetic
Show Abstract · Added April 2, 2019
BACKGROUND - Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E.
METHODS - Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed.
RESULTS - Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
CONCLUSIONS - Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress.
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MeSH Terms
Dimerization and phosphatase activity of calcyclin-binding protein/Siah-1 interacting protein: the influence of oxidative stress.
Topolska-Woś AM, Shell SM, Kilańczyk E, Szczepanowski RH, Chazin WJ, Filipek A
(2015) FASEB J 29: 1711-24
MeSH Terms: Amino Acid Sequence, Animals, Blotting, Western, Calcium-Binding Proteins, Flow Cytometry, Fluorescent Antibody Technique, Immunoprecipitation, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Molecular Sequence Data, Neuroblastoma, Oxidative Stress, Phosphorylation, Protein Conformation, Protein Multimerization, Protein Processing, Post-Translational, Proteins, Scattering, Small Angle, Sequence Homology, Amino Acid, Spectroscopy, Fourier Transform Infrared, Tumor Cells, Cultured
Show Abstract · Added February 5, 2016
CacyBP/SIP [calcyclin-binding protein/Siah-1 [seven in absentia homolog 1 (Siah E3 ubiquitin protein ligase 1)] interacting protein] is a multifunctional protein whose activity includes acting as an ERK1/2 phosphatase. We analyzed dimerization of mouse CacyBP/SIP in vitro and in mouse neuroblastoma cell line (NB2a) cells, as well as the structure of a full-length protein. Moreover, we searched for the CacyBP/SIP domain important for dimerization and dephosphorylation of ERK2, and we analyzed the role of dimerization in ERK1/2 signaling in NB2a cells. Cell-based assays showed that CacyBP/SIP forms a homodimer in NB2a cell lysate, and biophysical methods demonstrated that CacyBP/SIP forms a stable dimer in vitro. Data obtained using small-angle X-ray scattering supported a model in which CacyBP/SIP occupies an anti-parallel orientation mediated by the N-terminal dimerization domain. Site-directed mutagenesis established that the N-terminal domain is indispensable for full phosphatase activity of CacyBP/SIP. We also demonstrated that the oligomerization state of CacyBP/SIP as well as the level of post-translational modifications and subcellular distribution of CacyBP/SIP change after activation of the ERK1/2 pathway in NB2a cells due to oxidative stress. Together, our results suggest that dimerization is important for controlling phosphatase activity of CacyBP/SIP and for regulating the ERK1/2 signaling pathway.
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22 MeSH Terms
The microfluidic multitrap nanophysiometer for hematologic cancer cell characterization reveals temporal sensitivity of the calcein-AM efflux assay.
Byrd TF, Hoang LT, Kim EG, Pfister ME, Werner EM, Arndt SE, Chamberlain JW, Hughey JJ, Nguyen BA, Schneibel EJ, Wertz LL, Whitfield JS, Wikswo JP, Seale KT
(2014) Sci Rep 4: 5117
MeSH Terms: Animals, Calcium-Binding Proteins, Cell Separation, Equipment Design, Equipment Failure Analysis, Flow Cytometry, Fluoresceins, Humans, Jurkat Cells, Leukemia, T-Cell, Microfluidic Analytical Techniques, Nanotechnology, Optical Tweezers, Reproducibility of Results, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added February 2, 2015
Cytometric studies utilizing flow cytometry or multi-well culture plate fluorometry are often limited by a deficit in temporal resolution and a lack of single cell consideration. Unfortunately, many cellular processes, including signaling, motility, and molecular transport, occur transiently over relatively short periods of time and at different magnitudes between cells. Here we demonstrate the multitrap nanophysiometer (MTNP), a low-volume microfluidic platform housing an array of cell traps, as an effective tool that can be used to study individual unattached cells over time with precise control over the intercellular microenvironment. We show how the MTNP platform can be used for hematologic cancer cell characterization by measuring single T cell levels of CRAC channel modulation, non-translational motility, and ABC-transporter inhibition via a calcein-AM efflux assay. The transporter data indicate that Jurkat T cells exposed to indomethacin continue to accumulate fluorescent calcein for over 60 minutes after calcein-AM is removed from the extracellular space.
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16 MeSH Terms
Lymphatic function is required prenatally for lung inflation at birth.
Jakus Z, Gleghorn JP, Enis DR, Sen A, Chia S, Liu X, Rawnsley DR, Yang Y, Hess PR, Zou Z, Yang J, Guttentag SH, Nelson CM, Kahn ML
(2014) J Exp Med 211: 815-26
MeSH Terms: Animals, Animals, Newborn, Calcium-Binding Proteins, DNA Primers, Echocardiography, Embryo, Mammalian, Fetus, Immunohistochemistry, Lung, Lung Compliance, Lymphatic System, Lymphography, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Pulmonary Edema, Real-Time Polymerase Chain Reaction, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor Receptor-3
Show Abstract · Added January 20, 2015
Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.
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19 MeSH Terms
Jagged1 is essential for osteoblast development during maxillary ossification.
Hill CR, Yuasa M, Schoenecker J, Goudy SL
(2014) Bone 62: 10-21
MeSH Terms: Animals, Bone Density, Bone Morphogenetic Proteins, Calcification, Physiologic, Calcium, Calcium-Binding Proteins, Cell Differentiation, Embryo, Mammalian, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Maxilla, Membrane Proteins, Mesoderm, Mice, Knockout, Organ Size, Osteoblasts, Osteogenesis, Palate, Receptors, Fc, Receptors, Notch, Serrate-Jagged Proteins, Signal Transduction, X-Ray Microtomography
Show Abstract · Added May 28, 2014
Maxillary hypoplasia occurs due to insufficient maxillary intramembranous ossification, leading to poor dental occlusion, respiratory obstruction and cosmetic deformities. Conditional deletion of Jagged1 (Jag1) in cranial neural crest (CNC) cells using Wnt1-cre; Jagged1(f/f) (Jag1CKO) led to maxillary hypoplasia characterized by intrinsic differences in bone morphology and density using μCT evaluation. Jag1CKO maxillas revealed altered collagen deposition, delayed ossification, and reduced expression of early and late determinants of osteoblast development during maxillary ossification. In vitro bone cultures on Jag1CKO mouse embryonic maxillary mesenchymal (MEMM) cells demonstrated decreased mineralization that was also associated with diminished induction of osteoblast determinants. BMP receptor expression was dysregulated in the Jag1CKO MEMM cells suggesting that these cells were unable to respond to BMP-induced differentiation. JAG1-Fc rescued in vitro mineralization and osteoblast gene expression changes. These data suggest that JAG1 signaling in CNC-derived MEMM cells is required for osteoblast development and differentiation during maxillary ossification.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization.
Sivakumaran V, Stanley BA, Tocchetti CG, Ballin JD, Caceres V, Zhou L, Keceli G, Rainer PP, Lee DI, Huke S, Ziolo MT, Kranias EG, Toscano JP, Wilson GM, O'Rourke B, Kass DA, Mahaney JE, Paolocci N
(2013) Antioxid Redox Signal 19: 1185-97
MeSH Terms: Adenosine Triphosphate, Animals, Antioxidants, Calcium, Calcium Signaling, Calcium-Binding Proteins, Cardiotonic Agents, Cyclic AMP-Dependent Protein Kinases, Disulfides, Heart Ventricles, In Vitro Techniques, Mice, Mice, Knockout, Microsomes, Myocytes, Cardiac, Nitrogen Oxides, Oxidation-Reduction, Phosphorylation, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, Sarcoplasmic Reticulum, Sarcoplasmic Reticulum Calcium-Transporting ATPases
Show Abstract · Added May 27, 2014
AIMS - Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts.
RESULTS - Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted β-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln(-/-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available.
INNOVATION - HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a.
CONCLUSIONS - PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts.
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25 MeSH Terms
SPARCL1 suppresses metastasis in prostate cancer.
Xiang Y, Qiu Q, Jiang M, Jin R, Lehmann BD, Strand DW, Jovanovic B, DeGraff DJ, Zheng Y, Yousif DA, Simmons CQ, Case TC, Yi J, Cates JM, Virostko J, He X, Jin X, Hayward SW, Matusik RJ, George AL, Yi Y
(2013) Mol Oncol 7: 1019-30
MeSH Terms: Animals, Calcium-Binding Proteins, Cell Line, Tumor, Extracellular Matrix Proteins, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Male, Meta-Analysis as Topic, Mice, Mice, SCID, Neoplasm Metastasis, Neoplasm Transplantation, Prostatic Neoplasms, Tumor Suppressor Proteins
Show Abstract · Added December 10, 2013
PURPOSE - Metastasis, the main cause of death from cancer, remains poorly understood at the molecular level.
EXPERIMENTAL DESIGN - Based on a pattern of reduced expression in human prostate cancer tissues and tumor cell lines, a candidate suppressor gene (SPARCL1) was identified. We used in vitro approaches to determine whether overexpression of SPARCL1 affects cell growth, migration, and invasiveness. We then employed xenograft mouse models to analyze the impact of SPARCL1 on prostate cancer cell growth and metastasis in vivo.
RESULTS - SPARCL1 expression did not inhibit tumor cell proliferation in vitro. By contrast, SPARCL1 did suppress tumor cell migration and invasiveness in vitro and tumor metastatic growth in vivo, conferring improved survival in xenograft mouse models.
CONCLUSIONS - We present the first in vivo data suggesting that SPARCL1 suppresses metastasis of prostate cancer.
Copyright © 2013 Federation of European Biochemical Societies. All rights reserved.
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15 MeSH Terms