scholarly journals Notch1 signaling stimulates proliferation of immature cardiomyocytes

2008 ◽  
Vol 183 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Chiara Collesi ◽  
Lorena Zentilin ◽  
Gianfranco Sinagra ◽  
Mauro Giacca
Keyword(s):  
Notch Signaling ◽  
Cardiac Myocytes ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Constitutive Expression ◽  
Neonatal Rat ◽  
Proliferative Potential ◽  
Rat Cardiomyocytes

The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic, fetal, and early neonatal life appears of paramount interest in regard to exploiting this information to promote cardiac regeneration. Here, we show that the proliferative potential of neonatal rat cardiomyocytes is powerfully stimulated by the sustained activation of the Notch pathway. We found that Notch1 is expressed in proliferating ventricular immature cardiac myocytes (ICMs) both in vitro and in vivo, and that the number of Notch1-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled the expression of its Jagged1 ligand on non-myocyte supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion. Maintenance or reactivation of Notch signaling in cardiac myocytes might represent an interesting target for innovative regenerative therapy.

scholarly journals NBS1 interacts with Notch signaling in neuronal homeostasis

2020 ◽  
Vol 48 (19) ◽  
pp. 10924-10939
Author(s):  
Zhong-Wei Zhou ◽  
Murat Kirtay ◽  
Nadine Schneble ◽  
George Yakoub ◽  
Mingmei Ding ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Notch Pathway ◽  
Direct Consequence ◽  
Nijmegen Breakage Syndrome ◽  
Neuron Development ◽  
Genetic Ablation ◽  
Notch Activity ◽  
And Migration

Abstract NBS1 is a critical component of the MRN (MRE11/RAD50/NBS1) complex, which regulates ATM- and ATR-mediated DNA damage response (DDR) pathways. Mutations in NBS1 cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), of which neuronal deficits, including microcephaly and intellectual disability, are classical hallmarks. Given its function in the DDR to ensure proper proliferation and prevent death of replicating cells, NBS1 is essential for life. Here we show that, unexpectedly, Nbs1 deletion is dispensable for postmitotic neurons, but compromises their arborization and migration due to dysregulated Notch signaling. We find that Nbs1 interacts with NICD-RBPJ, the effector of Notch signaling, and inhibits Notch activity. Genetic ablation or pharmaceutical inhibition of Notch signaling rescues the maturation and migration defects of Nbs1-deficient neurons in vitro and in vivo. Upregulation of Notch by Nbs1 deletion is independent of the key DDR downstream effector p53 and inactivation of each MRN component produces a different pattern of Notch activity and distinct neuronal defects. These data indicate that neuronal defects and aberrant Notch activity in Nbs1-deficient cells are unlikely to be a direct consequence of loss of MRN-mediated DDR function. This study discloses a novel function of NBS1 in crosstalk with the Notch pathway in neuron development.

scholarly journals MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway

2017 ◽  
Vol 24 (8) ◽  
pp. 1431-1442 ◽  
Author(s):  
Xiaoyun Chen ◽  
Wei Xiao ◽  
Weirong Chen ◽  
Xialin Liu ◽  
Mingxing Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Lens Epithelial Cells ◽  
Mesenchymal Transition ◽  
Fibrotic Diseases

Abstract Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

scholarly journals Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1011-1023 ◽  
Author(s):  
Hui Liu ◽  
Xibo Jing ◽  
Aiqiao Dong ◽  
Baobao Bai ◽  
Haiyan Wang
Keyword(s):  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Ros Production ◽  
Rat Cardiomyocytes ◽  
Doxorubicin Treatment ◽  
Myocardial Apoptosis

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

Mechanical stimulation of organogenic cardiomyocyte growth in vitro

1996 ◽  
Vol 270 (5) ◽  
pp. C1284-C1292 ◽  
Author(s):  
H. H. Vandenburgh ◽  
R. Solerssi ◽  
J. Shansky ◽  
J. W. Adams ◽  
S. A. Henderson
Keyword(s):  
Mechanical Load ◽  
Mechanical Stretch ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Heart Cells ◽  
Mechanical Stimuli ◽  
Rat Cardiomyocytes ◽  
Morphological Alterations

Adherent cultures of neonatal rat cardiomyocytes were subjected to progressive, unidirectional lengthening for 2-4 days in serum-containing medium. This mechanical stretch (25% increase in initial length each day) simulates the eccentric mechanical load placed on in vivo heart cells by increases in postnatal blood pressure and volume. The in vitro mechanical stimuli initiated a number of morphological alterations in the confluent cardiomyocyte population which were similar to those occurring during in vivo heart growth. These include cardiomyocyte organization into parallel arrays of rod-shaped cells, increased cardiomyocyte binucleation, and cardiomyocyte hypertrophy by longitudinal cell growth. Stretch stimulated DNA synthesis in the noncardiomyocyte population but not in the cardiomyocytes. Myosin heavy chain (MHC) content increased 62% over 4 days of stretch and included increased accumulation of both fetal beta-MHC and adult alpha-MHC isoforms. This new model of stretch-induced cardiomyocyte hypertrophy may assist in examining some of the complex mechanogenic growth processes that occur in the rapidly enlarging neonatal heart.

scholarly journals Notch pathway activation targets AML-initiating cell homeostasis and differentiation

2013 ◽  
Vol 210 (2) ◽  
pp. 301-319 ◽  
Author(s):  
Camille Lobry ◽  
Panagiotis Ntziachristos ◽  
Delphine Ndiaye-Lobry ◽  
Philmo Oh ◽  
Luisa Cimmino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Notch Signaling ◽  
Myeloproliferative Neoplasms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Pathway Activation ◽  
Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

scholarly journals Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

2019 ◽  
Author(s):  
Kamila Kwiecien ◽  
Piotr Brzoza ◽  
Pawel Majewski ◽  
Izabella Skulimowska ◽  
Kamil Bednarczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Phase ◽  
Molecular Mechanisms ◽  
Retinoic Acid Receptor ◽  
Constitutive Expression ◽  
Sequencing Analysis ◽  
Mrna Levels ◽  
Pleiotropic Actions

AbstractChemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention over the past few years due to its multilevel impact on metabolism and immune responses. The pleiotropic actions of chemerin include chemotaxis of dendritic cells, macrophages and natural killers (NK) subsets, bactericidal activity as well as regulation of adipogenesis and glucose metabolism. Therefore, reflecting the pleiotropic actions of chemerin, expression of RARRES2 is regulated by a variety of inflammatory and metabolic mediators. However, for most cell types, the molecular mechanisms controlling constitutive and regulated chemerin expression are poorly characterized. Here we show that RARRES2 mRNA levels in murine adipocytes are upregulated in vitro and in vivo by acute-phase cytokines, IL-1β and OSM. In contrast to adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effect of IL-1β and OSM on chemerin expression is specific to fat tissue. Moreover, we show that DNA methylation controls the constitutive expression of chemerin. Bisulfite sequencing analysis showed low methylation levels within −735 to +258 bp of the murine RARRES2 gene promoter in unstimulated adipocytes and hepatocytes. In contrast to these cells, the RARRES2 promoter is highly methylated in B lymphocytes, cells that do not produce chemerin. Together, our findings reveal previously uncharacterized mediators and mechanisms controlling chemerin expression in various cells.

scholarly journals Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

2020 ◽  
Author(s):  
Wahafu Alafate ◽  
Dongze Xu ◽  
Wei Wu ◽  
Jianyang Xiang ◽  
Xudong Ma ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Acquired Resistance ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Gene Expression Omnibus ◽  
Primary Brain Tumor ◽  
Biological Behavior ◽  
Clinical Samples

Abstract BackgroundGlioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

scholarly journals Structural and functional analysis of the repressor complex in the Notch signaling pathway ofDrosophila melanogaster

2011 ◽  
Vol 22 (17) ◽  
pp. 3242-3252 ◽  
Author(s):  
Dieter Maier ◽  
Patricia Kurth ◽  
Adriana Schulz ◽  
Andrew Russell ◽  
Zhenyu Yuan ◽  
...  
Keyword(s):  
Cell Culture ◽  
Notch Signaling ◽  
Target Genes ◽  
Notch Pathway ◽  
Structural Similarity ◽  
Receptor Activation ◽  
Notch Signaling Pathway ◽  
Repressor Complex

In metazoans, the highly conserved Notch pathway drives cellular specification. On receptor activation, the intracellular domain of Notch assembles a transcriptional activator complex that includes the DNA-binding protein CSL, a composite of human C-promoter binding factor 1, Suppressor of Hairless of Drosophila melanogaster [Su(H)], and lin-12 and Glp-1 phenotype of Caenorhabditis elegans. In the absence of ligand, CSL represses Notch target genes. However, despite the structural similarity of CSL orthologues, repression appears largely diverse between organisms. Here we analyze the Notch repressor complex in Drosophila, consisting of the fly CSL protein, Su(H), and the corepressor Hairless, which recruits general repressor proteins. We show that the C-terminal domain of Su(H) is necessary and sufficient for forming a high-affinity complex with Hairless. Mutations in Su(H) that affect interactions with Notch and Mastermind have no effect on Hairless binding. Nonetheless, we demonstrate that Notch and Hairless compete for CSL in vitro and in cell culture. In addition, we identify a site in Hairless that is crucial for binding Su(H) and subsequently show that this Hairless mutant is strongly impaired, failing to properly assemble the repressor complex in vivo. Finally, we demonstrate Hairless-mediated inhibition of Notch signaling in a cell culture assay, which hints at a potentially similar repression mechanism in mammals that might be exploited for therapeutic purposes.

Abstract 15925: Newt Exosomes are Bioactive on Mammalian Heart, Enhancing Proliferation of Rat Cardiomyocytes and Improving Recovery After Myocardial Infarction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Eleni Tseliou ◽  
Liu Weixin ◽  
Jackelyn Valle ◽  
Baiming Sun ◽  
Maria Mirotsou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Critical Role ◽  
Dermal Fibroblasts ◽  
Neonatal Rat ◽  
Cardiomyocyte Proliferation ◽  
Rat Cardiomyocytes ◽  
Mesodermal Cell ◽  
Wistar Kyoto

Introduction: Adult newts can regenerate amputated cardiac tissue (and whole limbs) without fibrosis, unlike adult mammals which lack such regenerative capacity. Exosomes are nanoparticles which mediate intercellular communication and play a critical role in therapeutic regeneration. Hypothesis: We isolated exosomes from a newt mesodermal cell line, and evaluated their bioactivity in rat models. Methods: A1 cells, derived from the amputated limb buds of Notopthalmus viridescense (Brockes JP, 1988), were expanded in culture. Exosomes were isolated by polyethylene glycol precipitation of A1-conditioned serum-free media (or media conditioned by human dermal fibroblasts [DF] as a control) followed by centrifugation. Bioactivity was tested in vitro on neonatal rat ventricular myocytes (NRVM), and in vivo on acute myocardial infarction in Wistar-Kyoto rats (250μg or 500μg of A1-exosomes or vehicle [placebo] injected intramyocardially). Functional and histological analyses were performed 3 weeks after therapy. Results: A1-conditioned media yielded ~2.8±1Billion particles/ml of 129±1.1 nm diameter. In vitro, A1-exosomes increased the proliferative capacity of NRVM compared to DF-exosomes (4.98±0.89% vs 0.77±0.33%, p=0.035). Priming of DFs with A1-exosomes increased SDF-1 secretion compared to DF-exosomes (755±117pg/ml vs.368±21pg/ml, p=0.03). In vivo, both A1-exosome doses increased cardiac function compared to placebo (EF= 46±1% in 250μg, 49±4% in 500μg vs 36±1% in placebo, p=0.045 by ANOVA). Scar size was markedly decreased (11±1% in 250μg, 9±2% in 500μg vs 18±2% in placebo, p=0.006 by ANOVA), and infarct wall thickness was increased after A1-exosome treatment (1.7±0.11mm in 250μg, 1.85±0.16mm in 500μg vs 1.17±0.11mm in Placebo, p=0.01 by ANOVA). Donor-specific antibodies were present at barely detectable levels in the serum of animals that had been injected with A1-exosomes. Conclusions: Newt exosomes stimulate rat cardiomyocyte proliferation and improve functional and structural outcomes in rats with myocardial infarction. Characterization of the RNA and protein content of newt exosomes, now in progress, may provide clues regarding conserved (or newt-unique) molecular mediators of therapeutic benefit.

Abstract 1828: Dyxin/Lmcd1 Mediates Cardiac Hypertrophy Both In Vitro And In Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Derk Frank ◽  
Robert Frauen ◽  
Christiane Hanselmann ◽  
Christian Kuhn ◽  
Rainer Will ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
The Novel ◽  
Rat Cardiomyocytes ◽  
A Genome

In order to identify new molecular mediators of cardiomyocyte hypertrophy, we performed a genome wide mRNA microarray screen of biomechanically stretched neonatal rat cardiomyocytes (NRCM). We found the novel sarcomeric LIM protein Dyxin/Lmcd1 being significantly upregulated (5.6x, p<0.001). Moreover, Dyxin was also significantly induced in several mouse models of myocardial hypertrophy including aortic banding, calcineurin overexpression and angiotensin stimulation, suggesting a potential role as a mediator of cardiac hypertrophy. To further test this hypothesis, we adenovirally overexpressed Dyxin in NRCM which potently induced cellular hypertrophy (150%, p<0.001) and the hypertrophic gene program (ANF, BNP). Consistent with an induction of calcineurin signalling, the calcineurin-responsive gene Rcan1– 4 (MCIP1.4) was found significantly upregulated (3.2x, p<0.001). Conversely, knockdown of Dyxin (−75% on protein level) via miRNA completely blunted the hypertrophic response to hypertrophic stimuli, including stretch and PE (both p<0.001). Furthermore, PE-mediated activation of calcineurin signaling (Upregulation of Rcan1– 4 by 7.3x, p<0.001) was completely blocked by knockdown of Dyxin. To confirm these results in vivo, we next generated transgenic mice with cardiac-restricted overexpression of Dyxin using the α -MHC promoter. Despite normal cardiac function as assessed by echocardiography, adult transgenic mice displayed significant cardiac hypertrophy in morphometrical analyses (3.9 vs. 3.5 mg/g LV/heart weight, n=8–11, p<0.05). This finding was supplemented by a robust induction of the hypertrophic gene program including ANF (3.7-fold, n=6, p=0.01) and α -skeletal actin (2.8-fold, n=6, p<0.05). Likewise, Rcan1– 4 was found upregulated (+112%, n=5, p<0.05), Taken together, we show that the novel sarcomeric z-disc protein Dyxin/Lmcd1 is significantly upregulated in several models of cardiac hypertrophy and potently induces cardiomyocyte hypertrophy both in vitro and in vivo. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway.

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