P4995Neuregulin-1 compensates for endothelial NO synthase deficiency in the heart and kidney

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Shakeri ◽  
S De Moudt ◽  
A J Leloup ◽  
G Jacobs ◽  
G R Y De Meyer ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Cell Types ◽  
Cardiovascular Development ◽  
Wild Type ◽  
Negative Effects ◽  
Knock Out ◽  
Neuregulin 1 ◽  
Cardioprotective Effects ◽  
To Receive ◽  
Knock Out Mouse

Abstract Background Decreased eNOS activity is the hallmark of endothelial dysfunction and is associated with cardiovascular and renal disorders. Besides NO, endothelial cells produce numerous other small molecules, peptides, and proteins, which modulate the function of adjacent cells. For instance, neuregulin-1 (NRG-1) is an endothelium-derived growth factor, which plays crucial roles in cardiovascular development, has cardioprotective properties, and induces growth and differentiation of cell types in different organs, including the kidney. Purpose Although the cardioprotective effects of endothelium-derived NO and NRG-1 are well established, their interaction is not clear. Therefore, we studied the interaction between the NO/eNOS and NRG-1/ErbB signalling pathways in a transgenic eNOS knock-out mouse model (eNOS−/−) treated with subpressor doses of angiotensin II (AngII). Methods eNOS−/− mice and their wild type (WT) littermates (n=64, 15 weeks old) were randomized for implantation of osmotic minipumps with AngII (400 ng/kg.min) for 28 days or sham surgery. Mice were randomized to receive either daily NRG-1 injections (20 μg/kg, intraperitoneal) or vehicle for 4 weeks (n=8/group). Hypertrophy and fibrosis were measured in left ventricle (LV) and kidneys using echography and immunohistochemical staining. Results Although blood pressure was higher in eNOS−/− mice compared to their WT littermates, it was unaffected by a subpressor dose of AngII. Masson's trichrome staining showed that AngII significantly increased LV (interstitial and perivascular) and renal fibrosis in eNOS−/− mice, but not in WT controls (see figure for LV data). NRG-1 reversed this AngII-induced LV and renal fibrosis caused by eNOS deficiency. There was also significant hypertrophy of LV and kidneys in eNOS−/− mice treated with AngII, which was again normalized by NRG-1 treatment. Moreover, NRG-1 significantly attenuated albuminuria induced by eNOS deficiency under AngII treatment. Conclusions This study demonstrates that the anti-fibrotic and anti-hypertrophic effects of NRG-1 are independent from the NO/eNOS pathway in both heart and kidney. Strikingly, NRG-1 is able to compensate for some of the negative effects of eNOS deficiency, at least in conditions of AngII stimulation. Acknowledgement/Funding supported by university of Antwerp

scholarly journals Modulation of the neuronal response to ischaemia by somatostatin analogues in wild-type and knock-out mouse retinas

2008 ◽  
Vol 106 (5) ◽  
pp. 2224-2235 ◽  
Author(s):  
Davide Cervia ◽  
Davide Martini ◽  
Chiara Ristori ◽  
Elisabetta Catalani ◽  
Anna Maria Timperio ◽  
...  
Keyword(s):  
Neuronal Response ◽  
Somatostatin Analogues ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mouse

Abstract P155: HSF-1 Deletion Induces MDR1 Gene in the Heart and Protects from Doxorubicin-Induced Cardiotoxicity

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Karthikeyan Krishnamurthy ◽  
Lawrence Druhan ◽  
Govindasamy Ilangovan
Keyword(s):  
Cardiac Dysfunction ◽  
Mdr1 Gene ◽  
Heat Shock Factor 1 ◽  
Wild Type ◽  
Rt Pcr ◽  
Glycoprotein P ◽  
Knock Out ◽  
P Glycoprotein ◽  
Mdr1 Gene Expression ◽  
Knock Out Mouse

Heat shock factor 1 (HSF-1) has been found to be a frontline responder of different stresses in eukaryotic cells. Deletion of HSF-1 has been reported to develop defects in mice. In the present work we report that deletion of HSF-1 induced multidrug resistance 1 (MDR1) gene and P-glycoprotein (P-gp) expression. Both RT-PCR and western blotting, confirmed the higher level of MDR1 gene expression and P-gp protein in HSF-1 knock out mouse hearts. P-gp is well known ATP binding cassette, which extrudes intracellular drugs upon binding ATP. Hence the phenotype of the P-gp pump in HSF-1 −/− mice was studied in the form of Doxorubicin (Dox) extrusion in the heart. Cardiomyocytes isolated from HSF-1 −/− and HSF-1 +/− mice retained very less intracellular Dox, compared to wild type counterparts. Similarly, both HSF-1 +/− and HSF-1 −/− mice were less susceptible for Dox-induced cardiotoxicity, as seen from reduced cardiac dysfunction in these group against Dox (as confirmed by cardiac MRI and echocardiography). Further confirmatory studies revealed that deletion of HSF-1 enhances NF-B, which subsequently induces MDR1 gene. These results reveal that inactivation of HSF-1 in the heart will be a potential approach to prevent Dox-induced cardiotoxicity.

Functional characterization of the H+/K+ ATPase in wild type and gastrin knock-out mice

2007 ◽  
Vol 45 (05) ◽  
Author(s):  
A Schnur ◽  
P Hegyi ◽  
V Venglovecz ◽  
Z Rakonczay ◽  
I Ignáth ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice

Brain immune cells characterization in UCMS exposed P2X7 knock-out mouse

2021 ◽  
Vol 94 ◽  
pp. 159-174
Author(s):  
Romain Troubat ◽  
Samuel Leman ◽  
Katleen Pinchaud ◽  
Alexandre Surget ◽  
Pascal Barone ◽  
...  
Keyword(s):  
Immune Cells ◽  
Knock Out ◽  
Knock Out Mouse

scholarly journals Effects of cofD gene knock-out on the methanogenesis of Methanobrevibacter ruminantium

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jian Ma ◽  
Xueying Wang ◽  
Ting Zhou ◽  
Rui Hu ◽  
Huawei Zou ◽  
...  
Keyword(s):  
Growth Rate ◽  
Specific Growth ◽  
Production Capacity ◽  
Maximum Amount ◽  
Logarithmic Phase ◽  
Wild Type ◽  
Knock Out ◽  
Maximum Biomass ◽  
Reproductive Ability ◽  
Methanobrevibacter Ruminantium

AbstractThis study aimed to investigate the effects of cofD gene knock-out on the synthesis of coenzyme F420 and production of methane in Methanobrevibacter ruminantium (M. ruminantium). The experiment successfully constructed a cofD gene knock-out M. ruminantium via homologous recombination technology. The results showed that the logarithmic phase of mutant M. ruminantium (12 h) was lower than the wild-type (24 h). The maximum biomass and specific growth rate of mutant M. ruminantium were significantly lower (P < 0.05) than those of wild-type, and the maximum biomass of mutant M. ruminantium was approximately half of the wild-type; meanwhile, the proliferation was reduced. The synthesis amount of coenzyme F420 of M. ruminantium was significantly decreased (P < 0.05) after the cofD gene knock-out. Moreover, the maximum amount of H2 consumed and CH4 produced by mutant were 14 and 2% of wild-type M. ruminantium respectively. In conclusion, cofD gene knock-out induced the decreased growth rate and reproductive ability of M. ruminantium. Subsequently, the synthesis of coenzyme F420 was decreased. Ultimately, the production capacity of CH4 in M. ruminantium was reduced. Our research provides evidence that cofD gene plays an indispensable role in the regulation of coenzyme F420 synthesis and CH4 production in M. ruminantium.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Microtubule–microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes

2016 ◽  
Vol 113 (34) ◽  
pp. E4995-E5004 ◽  
Author(s):  
Wen Lu ◽  
Michael Winding ◽  
Margot Lakonishok ◽  
Jill Wildonger ◽  
Vladimir I. Gelfand
Keyword(s):  
Cytoplasmic Streaming ◽  
Cell Types ◽  
Nurse Cells ◽  
Wild Type ◽  
Actin Cortex ◽  
Microtubule Motor ◽  
Multiple Cell ◽  
Cytoplasmic Microtubules ◽  
Two Populations

Cytoplasmic streaming in Drosophila oocytes is a microtubule-based bulk cytoplasmic movement. Streaming efficiently circulates and localizes mRNAs and proteins deposited by the nurse cells across the oocyte. This movement is driven by kinesin-1, a major microtubule motor. Recently, we have shown that kinesin-1 heavy chain (KHC) can transport one microtubule on another microtubule, thus driving microtubule–microtubule sliding in multiple cell types. To study the role of microtubule sliding in oocyte cytoplasmic streaming, we used a Khc mutant that is deficient in microtubule sliding but able to transport a majority of cargoes. We demonstrated that streaming is reduced by genomic replacement of wild-type Khc with this sliding-deficient mutant. Streaming can be fully rescued by wild-type KHC and partially rescued by a chimeric motor that cannot move organelles but is active in microtubule sliding. Consistent with these data, we identified two populations of microtubules in fast-streaming oocytes: a network of stable microtubules anchored to the actin cortex and free cytoplasmic microtubules that moved in the ooplasm. We further demonstrated that the reduced streaming in sliding-deficient oocytes resulted in posterior determination defects. Together, we propose that kinesin-1 slides free cytoplasmic microtubules against cortically immobilized microtubules, generating forces that contribute to cytoplasmic streaming and are essential for the refinement of posterior determinants.

Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

2021 ◽  
Author(s):  
Hadis Shakeri ◽  
Jente R.A. Boen ◽  
Sofie De Moudt ◽  
Jhana O. Hendrickx ◽  
Arthur J.A. Leloup ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Fibrosis ◽  
Separate Experiment ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Paracrine Factor ◽  
Renal Hypertrophy ◽  
Neuregulin 1 ◽  
Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

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