scholarly journals Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

2008 ◽  
Vol 295 (5) ◽  
pp. H1905-H1916 ◽  
Author(s):  
Andrianos Kontogeorgis ◽  
Xiaodong Li ◽  
Eunice Y. Kang ◽  
Jonathan E. Feig ◽  
Marc Ponzio ◽  
...  
Keyword(s):  
Gap Junction ◽  
Ventricular Myocytes ◽  
Critical Role ◽  
Mouse Heart ◽  
Wild Type ◽  
Short Term ◽  
Wild Type Littermate ◽  
Cx43 Expression ◽  
Significant Prolongation ◽  
Electrophysiological Effects

Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/−; 66% mean reduction in Cx43) mice for 6 h at 10–15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/− myocytes had significantly shorter action potential durations (APD) and increased steady-state ( Iss) and inward rectifier ( IK1) potassium currents compared with those of wild-type littermate cells. In Cx43+/− hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/− hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.

scholarly journals Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

2012 ◽  
Vol 302 (4) ◽  
pp. H934-H952 ◽  
Author(s):  
Polina S. Petkova-Kirova ◽  
Barry London ◽  
Guy Salama ◽  
Randall L. Rasmusson ◽  
Vladimir E. Bondarenko
Keyword(s):  
Heart Failure ◽  
Gap Junction ◽  
Ventricular Myocytes ◽  
Mouse Heart ◽  
Intercellular Coupling ◽  
Human Heart Failure ◽  
Tnf Α ◽  
Cycle Lengths ◽  
Factor Α ◽  
Junction Conductance

Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca2+ handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca2+ handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca2+ handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na+ current ( INa) amplitude. All model tissues were examined for susceptibility to Ca2+ alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca2+ alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca2+ alternans was attributed to the prolonged AP, resulting in larger inactivation of INa, and to the decreased SR Ca2+ uptake and corresponding smaller SR Ca2+ load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.

scholarly journals PTX3 Deficiency Promotes Enhanced Accumulation and Function of CD11c+CD11b+ DCs in a Murine Model of Allergic Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jyoti Balhara ◽  
Latifa Koussih ◽  
Ashfaque Mohammed ◽  
Lianyu Shan ◽  
Bouchaib Lamkhioued ◽  
...  
Keyword(s):  
Murine Model ◽  
Allergic Inflammation ◽  
Cd4 T Cell ◽  
Wild Type ◽  
Short Term ◽  
Wild Type Littermate ◽  
Dominant Phenotype ◽  
Enhanced Expression ◽  
T Cell Survival ◽  
And Function

PTX3 is a unique member of the long pentraxins family and plays an indispensable role in regulating the immune system. We previously showed that PTX3 deletion aggravates allergic inflammation via a Th17 -dominant phenotype and enhanced CD4 T cell survival using a murine model of ovalbumin (OVA) induced allergic inflammation. In this study, we identified that upon OVA exposure, increased infiltration of CD11c+CD11b+ dendritic cells (DCs) was observed in the lungs of PTX3-/- mice compared to wild type littermate. Further analysis showed that a short-term OVA exposure led to an increased number of bone marrow common myeloid progenitors (CMP) population concomitantly with increased Ly6Chigh CCR2high monocytes and CD11c+CD11b+ DCs in the lungs. Also, pulmonary CD11c+CD11b+ DCs from OVA-exposed PTX3-/- mice exhibited enhanced expression of maturation markers, chemokines receptors CCR2, and increased OVA uptake and processing compared to wild type controls. Taken together, our data suggest that PTX3 deficiency heightened lung CD11c+CD11b+DC numbers and function, hence exacerbating airway inflammatory response.

Critical Role of CIB1 in Endothelial Cell Function and In Vivo Ischemia-Induced Angiogenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1800-1800
Author(s):  
Mohamed A. Zayed ◽  
Andrew McFadden ◽  
Weiping Yuan ◽  
Mary E. Hartnett ◽  
Dan Chalothorn ◽  
...  
Keyword(s):  
Hind Limb ◽  
Ex Vivo ◽  
Critical Role ◽  
Tube Formation ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Retinal Angiogenesis

Abstract CIB1, a 22kDa EF-hand containing calcium binding protein, was originally identified in a yeast two-hybrid screen as a binding partner for the cytoplasmic tail of the platelet integrin αIIb. CIB1 also associates with a number of kinases and modulates their activity, suggesting that CIB1 is an important regulatory molecule. Recently, we found that CIB1 is expressed in multiple endothelial cell (EC) types. We therefore tested the role of CIB1 in EC function in vitro, and in angiogenesis both ex vivo and in vivo. To test the role of CIB1 in EC function in vitro, we reduced endogenous CIB1 levels in ECs by RNA interference with an shRNA-delivered by lentivirus. CIB1 depletion significantly decreased EC haptotaxis on fibronectin and EC vascular tube formation on growth factor-reduced Matrigel. Treatment with FGF-2, an angiogenic factor, did not counter the observed inhibition of haptotaxis and tube formation by shRNA against CIB1. However, CIB1 overexpression enhanced FGF-2-induced EC haptotaxis relative to control cells. Similarly, ECs derived from CIB1 null mice exhibited a significant decrease in haptotaxis, tube formation, and proliferation compared to ECs isolated from wild-type littermate controls. In ex vivo aortic ring and tibialis anterior muscle culture assays, CIB1 null cultures supplemented with serum or FGF-2 demonstrated reduced blood vessel sprouting compared to wild-type littermate control cultures. Finally, in vivo assays for hyperoxic retinal angiogenesis and hind-limb induced-ischemia revealed a decrease in post-ischemia retinal neovascularization and Doppler hind-limb blood perfusion recovery, although developmental retinal angiogenesis in CIB1 null mice appeared normal. In conclusion, these findings support a critical role for CIB1 in EC function that appears to be important for ischemia-induced angiogenesis.

scholarly journals Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

2017 ◽  
Vol 114 (8) ◽  
pp. E1345-E1354 ◽  
Author(s):  
Myong-Ho Jeong ◽  
Hyun-Ji Kim ◽  
Jung-Hoon Pyun ◽  
Kyu-Sil Choi ◽  
Dong I. Lee ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Gap Junction ◽  
Cardiac Remodeling ◽  
Connexin 43 ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Cell Surface Receptor ◽  
Cx43 Expression ◽  
Rat Cardiomyocytes ◽  
Junction Protein

On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon−/−hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon−/−hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon−/−cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon−/−hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.

scholarly journals Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

2019 ◽  
Author(s):  
Jamie E. Abato ◽  
Mahira Moftah ◽  
Greg O. Cron ◽  
Patrice D. Smith ◽  
Nafisa M. Jadavji
Keyword(s):  
Ischemic Stroke ◽  
Brain Tissue ◽  
Cellular Response ◽  
Methylenetetrahydrofolate Reductase ◽  
Critical Role ◽  
Antioxidant Response ◽  
Related Factor ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Damage Site

AbstractObjectiveElevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C➔T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/− mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.MethodsIn the present study, three-month-old male Mthfr+/− and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected.ResultsMthfr+/− animals used their non-impaired forepaw more during to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/− mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2 (SOD2).ConclusionsOur results suggest that Mthfr+/− mice are more vulnerable to PT-induced stroke damage through regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

scholarly journals Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function

2012 ◽  
Vol 23 (17) ◽  
pp. 3299-3311 ◽  
Author(s):  
Oscar Jara ◽  
Rodrigo Acuña ◽  
Isaac E. García ◽  
Jaime Maripillán ◽  
Vania Figueroa ◽  
...  
Keyword(s):  
Gap Junction ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Full Length ◽  
Intermediate Step ◽  
Wild Type ◽  
Gap Junction Channels ◽  
Junction Protein ◽  
And Function ◽  
Pore Domain

To identify motifs involved in oligomerization of the gap junction protein Cx26, we studied individual transmembrane (TM) domains and the full-length protein. Using the TOXCAT assay for interactions of isolated TM α-helices, we found that TM1, a Cx26 pore domain, had a strong propensity to homodimerize. We identified amino acids Val-37–Ala-40 (VVAA) as the TM1 motif required for homodimerization. Two deafness-associated Cx26 mutations localized in this region, Cx26V37I and Cx26A40G, differentially affected dimerization. TM1-V37I dimerized only weakly, whereas TM1-A40G did not dimerize. When the full-length mutants were expressed in HeLa cells, both Cx26V37I and Cx26A40G formed oligomers less efficiently than wild-type Cx26. A Cx26 cysteine substitution mutant, Cx26V37C formed dithiothreitol-sensitive dimers. Substitution mutants of Val-37 formed intercellular channels with reduced function, while mutants of Ala-40 did not form functional gap junction channels. Unlike wild-type Cx26, neither Cx26V37I nor Cx26A40G formed functional hemichannels in low extracellular calcium. Thus the VVAA motif of Cx26 is critical for TM1 dimerization, hexamer formation, and channel function. The differential effects of VVAA mutants on hemichannels and gap junction channels imply that inter-TM interactions can differ in unapposed and docked hemichannels. Moreover, Cx26 oligomerization appears dependent on transient TM1 dimerization as an intermediate step.

The capacity of short term memory from an evolutionary perspective

2019 ◽  
Author(s):  
Majid Manoochehri
Keyword(s):  
Short Term Memory ◽  
Memory Span ◽  
Critical Role ◽  
Experimental Studies ◽  
Cognitive System ◽  
Evolutionary Approach ◽  
Evolutionary Perspective ◽  
Short Term ◽  
Term Memory

Memory span in humans has been intensely studied for more than a century. In spite of the critical role of memory span in our cognitive system, which intensifies the importance of fundamental determinants of its evolution, few studies have investigated it by taking an evolutionary approach. Overall, we know hardly anything about the evolution of memory components. In the present study, I briefly review the experimental studies of memory span in humans and non-human animals and shortly discuss some of the relevant evolutionary hypotheses.

scholarly journals Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3219
Author(s):  
Natalia I. Krupenko ◽  
Jaspreet Sharma ◽  
Halle M. Fogle ◽  
Peter Pediaditakis ◽  
Kyle C. Strickland ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Chemical Carcinogenesis ◽  
Dependent Manner ◽  
Wild Type ◽  
Liver Carcinogenesis ◽  
Wild Type Littermate ◽  
Tumor Multiplicity ◽  
Accelerate Growth ◽  
Putative Tumor Suppressor ◽  
Formyltetrahydrofolate Dehydrogenase

Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is commonly downregulated in human cancers through promoter methylation. We proposed that ALDH1L1 loss promotes malignant tumor growth. Here, we investigated the effect of the Aldh1l1 mouse knockout (Aldh1l1−/−) on hepatocellular carcinoma using a chemical carcinogenesis model. Fifteen-day-old male Aldh1l1 knockout mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with 20 μg/g body weight of DEN (diethylnitrosamine). Mice were sacrificed 10, 20, 28, and 36 weeks post-DEN injection, and livers were examined for tumor multiplicity and size. We observed that while tumor multiplicity did not differ between Aldh1l1−/− and Aldh1l1+/+ animals, larger tumors grew in Aldh1l1−/− compared to Aldh1l1+/+ mice at 28 and 36 weeks. Profound differences between Aldh1l1−/− and Aldh1l1+/+ mice in the expression of inflammation-related genes were seen at 10 and 20 weeks. Of note, large tumors from wild-type mice showed a strong decrease of ALDH1L1 protein at 36 weeks. Metabolomic analysis of liver tissues at 20 weeks showed stronger differences in Aldh1l1+/+ versus Aldh1l1−/− metabotypes than at 10 weeks, which underscores metabolic pathways that respond to DEN in an ALDH1L1-dependent manner. Our study indicates that Aldh1l1 knockout promoted liver tumor growth without affecting tumor initiation or multiplicity.

scholarly journals A Novel Load Forecasting Approach Based on Smart Meter Data Using Advance Preprocessing and Hybrid Deep Learning

2021 ◽  
Vol 11 (6) ◽  
pp. 2742
Author(s):  
Fatih Ünal ◽  
Abdulaziz Almalaq ◽  
Sami Ekici
Keyword(s):  
Deep Learning ◽  
Energy Consumption ◽  
Prediction Models ◽  
Short Term Memory ◽  
Critical Role ◽  
Load Forecasting ◽  
Unified Framework ◽  
Short Term ◽  
Planning And Scheduling ◽  
Short Term Load Forecasting

Short-term load forecasting models play a critical role in distribution companies in making effective decisions in their planning and scheduling for production and load balancing. Unlike aggregated load forecasting at the distribution level or substations, forecasting load profiles of many end-users at the customer-level, thanks to smart meters, is a complicated problem due to the high variability and uncertainty of load consumptions as well as customer privacy issues. In terms of customers’ short-term load forecasting, these models include a high level of nonlinearity between input data and output predictions, demanding more robustness, higher prediction accuracy, and generalizability. In this paper, we develop an advanced preprocessing technique coupled with a hybrid sequential learning-based energy forecasting model that employs a convolution neural network (CNN) and bidirectional long short-term memory (BLSTM) within a unified framework for accurate energy consumption prediction. The energy consumption outliers and feature clustering are extracted at the advanced preprocessing stage. The novel hybrid deep learning approach based on data features coding and decoding is implemented in the prediction stage. The proposed approach is tested and validated using real-world datasets in Turkey, and the results outperformed the traditional prediction models compared in this paper.

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