scholarly journals Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females

2022 ◽  
Vol 8 ◽  
Author(s):  
Nadine Norton ◽  
Katelyn A. Bruno ◽  
Damian N. Di Florio ◽  
Emily R. Whelan ◽  
Anneliese R. Hill ◽  
...  
Keyword(s):  
Heart Tissue ◽  
Trpc Channels ◽  
Male Mice ◽  
Wild Type ◽  
Cardiac Damage ◽  
Knock Out ◽  
Functional Changes ◽  
Female Mice ◽  
And Function ◽  
Deficient Mice

Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients.Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7. Cardiac function was determined by echocardiography.Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin.Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.

scholarly journals Cytochrome P450 Genes Are Differentially Expressed in Female and Male Hepatocyte Retinoid X Receptor α-Deficient Mice

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2311-2318 ◽  
Author(s):  
Yan Cai ◽  
Tiane Dai ◽  
Yan Ao ◽  
Tamiko Konishi ◽  
Kuang-Hsiang Chuang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Negative Impact ◽  
Retinoid X Receptor ◽  
Differentially Expressed ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Deficient Mice

Abstract To study the functional role of retinoid X receptor α (RXRα) in hepatocytes, hepatocyte RXRα-deficient mice have been established. Characterization has been performed on male mice. In this paper, we show that the expression of CYP450 genes is differentially expressed in male and female hepatocyte RXRα-deficient mice; male mice have reduced expression of cytochrome P450 (CYP) CYP4A, CYP3A, and CYP2B mRNAs, but females do not exhibit such phenotypes. To examine the hormonal effects on this sexual dimorphic phenotype, male and female mice were subjected to 17β-estradiol and 5α-dihydrotestosterone (DHT) treatment, respectively, and then the expression of the CYP450 genes was studied. Estradiol had no effect on protecting the hepatocyte RXRα-deficient mice from reduced expression of the CYP450 genes. In contrast, DHT induced hepatocyte RXRα-deficient female mice, but not wild-type female mice, to have the reduced expression of CYP450 mRNAs. In addition, castration prevented the mutant male mice from exhibiting reduced expression of CYP450 mRNAs. wild-type and mutant mouse livers from both genders express androgen receptors (ARs). By transient transfection, DHT-AR could inhibit RXRα-mediated transcription. Furthermore, by transfection and coimmunoprecipitation, RXR can interact with AR in vivo. These data suggest that testosterone has a negative impact on retinoid signaling when the level of RXRα is low, which may in turn reduce the expression of the CYP450 genes.

Treadmill running causes significant fiber damage in skeletal muscle of KATP channel-deficient mice

2005 ◽  
Vol 22 (2) ◽  
pp. 204-212 ◽  
Author(s):  
M. Thabet ◽  
T. Miki ◽  
S. Seino ◽  
J.-M. Renaud
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Treadmill Running ◽  
Wild Type ◽  
Connective Tissues ◽  
Fiber Damage ◽  
Hindlimb Muscles ◽  
Skeletal Muscle Fibers ◽  
And Function ◽  
Deficient Mice

Although it has been suggested that the ATP-sensitive K+ (KATP) channel protects muscle against function impairment, most studies have so far given little evidence for significant perturbation in the integrity and function of skeletal muscle fibers from inactive mice that lack KATP channel activity in their cell membrane. The objective was, therefore, to test the hypothesis that KATP channel-deficient skeletal muscle fibers become damaged when mice are subjected to stress. Wild-type and KATP channel-deficient mice (Kir6.2−/− mice) were subjected to 4–5 wk of treadmill running at either 20 m/min with 0° inclination or at 24 m/min with 20° uphill inclination. Muscles of all wild-type mice and of nonexercised Kir6.2−/− mice had very few fibers with internal nuclei. After 4–5 wk of treadmill running, there was little evidence for connective tissues and mononucleated cells in Kir6.2−/− hindlimb muscles, whereas the number of fibers with internal nuclei, which appear when damaged fibers are regenerated by satellite cells, was significantly higher in Kir6.2−/− than wild-type mice. Between 5% and 25% of the total number of fibers in Kir6.2−/− extensor digitum longus, plantaris, and tibialis muscles had internal nuclei, and most of such fibers were type IIB fibers. Contrary to hindlimb muscles, diaphragms of Kir6.2−/− mice that had run at 24 m/min had few fibers with internal nuclei, but mild to severe fiber damage was observed. In conclusion, the study provides for the first time evidence 1) that the KATP channels of skeletal muscle are essential to prevent fiber damage, and thus muscle dysfunction; and 2) that the extent of fiber damage is greater and the capacity of fiber regeneration is less in Kir6.2−/− diaphragm muscles compared with hindlimb muscles.

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Nanomechanics of Knockout Mouse Bones

2006 ◽  
Vol 975 ◽  
Author(s):  
N Beril Kavukcuoglu ◽  
Adrian B. Mann
Keyword(s):  
Mechanical Properties ◽  
Knockout Mice ◽  
Bone Mineralization ◽  
Bone Matrix ◽  
Wild Type ◽  
Knock Out ◽  
Bone Matrix Proteins ◽  
Fibrillin 1 ◽  
Deficient Mice ◽  
Radial Axis

ABSTRACTOsteocalcin (OC) and osteopontin (OPN) are among the most abundant non-collagenous bone matrix proteins. Both have drawn interest from investigators studying their function in osteoporosis and it is known that mutations of these proteins can also have dramatic effects on the properties of bone. Other proteins including fibrillin 1 and 2 (FBN2) have been less widely studied, but can be mutated in some individuals resulting in connective tissue disorders. It has been reported that abnormal fibrillin may play a role in decreased bone mass. In this study bones from osteopontin (OPN), osteocalcin (OC) and fibrillin-2 (FBN2) knockout mice have been investigated. The study has identified how these proteins affect the bone's nanomechanical properties (hardness and elastic modulus). Nanoindentation tests were performed on the radial axis of cortical femora bones from the knockout mice and their wildtype controls. The results showed that young (age< 12 weeks) OPN knock-out bones have significantly lower mechanical properties than wild-type bones indicate a crucial role for OPN in early bone mineralization. After 12 weeks of age, the OPN knockout and wild-type control bones did not show any statistical difference. In OC deficient mice the mechanical properties were found to increase in the cortical mid-shaft of femora from 1 year old mice, suggesting an increase in bone mineralization, but 3 month old FBN2 deficient mice bones showed a decrease in mechanical properties across the cortical radial axis of the mid- femora.

scholarly journals Localized Suppression of Inflammation at Sites of Helicobacter pylori Colonization

2011 ◽  
Vol 79 (10) ◽  
pp. 4186-4192 ◽  
Author(s):  
Alison L. Every ◽  
Garrett Z. Ng ◽  
Caroline D. Skene ◽  
Stacey N. Harbour ◽  
Anna K. Walduck ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Potential Model ◽  
Gastric Ph ◽  
Male Mice ◽  
Wild Type ◽  
Content Type ◽  
Female Mice ◽  
Gastric Corpus ◽  
Acid Secreting ◽  
H Pylori

ABSTRACTWhile gastric adenocarcinoma is the most serious consequence ofHelicobacter pyloriinfection, not all infected persons develop this pathology. Individuals most at risk of this cancer are those in whom the bacteria colonize the acid-secreting region of the stomach and subsequently develop severe inflammation in the gastric corpus. It has been reported anecdotally that male mice become infected with greater numbers ofH. pyloribacteria than female mice. While investigating this phenomenon, we found that increasedH. pyloriinfection densities in male mice were not related to antibody production, and this phenomenon was not normalized by gonadectomy. However, the gastric pH in male 129/Sv mice was significantly elevated compared with that in female mice. Differences in colonization were evident within 1 day postinfection and significantly arose due to colonization of the gastric corpus region in male mice. This provided a potential model for comparing the effect of corpus colonization on the development of gastritis. This was explored using two models ofH. pylori-induced inflammation, namely, 2-month infections ofMuc1−/−mice and 6-month infections of wild-type 129/Sv mice. WhileH. pyloriinfection of female mice induced a severe, corpus-predominant atrophic gastritis, to our surprise, male mice developed minimal inflammation despite being colonized with significantly moreH. pyloribacteria than female controls. Thus, colonization of the gastric corpus in male mice was associated with a loss of inflammation in that region. The suppression of inflammation concomitant with infection of the gastric corpus in male mice demonstrates a powerful localized suppression of inflammation induced at sites ofH. pyloricolonization.

scholarly journals Female mice respond to male ultrasonic ‘songs’ with approach behaviour

2009 ◽  
Vol 5 (5) ◽  
pp. 589-592 ◽  
Author(s):  
K. Hammerschmidt ◽  
K. Radyushkin ◽  
H. Ehrenreich ◽  
J. Fischer
Keyword(s):  
Male Mouse ◽  
Experimental Situation ◽  
Structure And Function ◽  
Ultrasonic Vocalizations ◽  
Male Mice ◽  
Playback Experiments ◽  
Female Mice ◽  
And Function ◽  
Female Responses ◽  
Artificial Control

The ultrasonic vocalizations of mice are attracting increasing attention, because they have been recognized as an informative readout in genetically modified strains. In addition, the observation that male mice produce elaborate sequences of ultrasonic vocalizations (‘song’) when exposed to female mice or their scents has sparked a debate as to whether these sounds are—in terms of their structure and function—analogous to bird song. We conducted playback experiments with cycling female mice to explore the function of male mouse songs. Using a place preference design, we show that these vocalizations elicited approach behaviour in females. In contrast, the playback of whistle-like artificial control sounds did not evoke approach responses. Surprisingly, the females also did not respond to pup isolation calls. In addition, female responses did not vary in relation to reproductive cycle, i.e. whether they were in oestrus or not. Furthermore, our data revealed a rapid habituation of subjects to the experimental situation, which stands in stark contrast to other species' responses to courtship vocalizations. Nevertheless, our results clearly demonstrate that male mouse songs elicit females' interest.

Disturbed Endothelial Blood-Bone Marrow-Barrier In Nox4 Deficient Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1169-1169
Author(s):  
Maren Weisser ◽  
Kerstin B. Kaufmann ◽  
Tomer Itkin ◽  
Linping Chen-Wichmann ◽  
Tsvee Lapidot ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Steady State ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Knock Out ◽  
Deficient Mice ◽  
Permeability State

Abstract Reactive oxygen species (ROS) have been implicated in the regulation of stemness of hematopoietic stem cells (HSC). HSC with long-term repopulating capabilities are characterized by low ROS levels, whereas increased ROS levels correlate with lineage specification and differentiation. Several tightly regulated sources of ROS production are well known among which are the NADPH oxidases (Nox). HSC are known to express Nox1, Nox2 and Nox4, however, their role in maintenance of stem cell potential or in the activation of differentiation programs are poorly understood. While Nox2 is activated in response to various extrinsic and intrinsic stimuli, mainly during infection and inflammation, Nox4 is constitutively active and is considered to be responsible for steady-state ROS production. Consequently, Nox4 deficiency might lower ROS levels at steady-state hematopoiesis and thereby could have an impact on HSC physiology. In this work we studied HSC homeostasis in Nox4 knock-out mice. Analysis of the hematopoietic stem and progenitor cell (HSPC) pool in the bone marrow (BM) revealed no significant differences in the levels of Lineage marker negative (Lin-) Sca-1+ ckit+ (LSK) and LSK-SLAM (LSK CD150+ CD48-) cells in Nox4 deficient mice compared to wild type (WT) C57BL/6J mice. HSPC frequency upon primary and secondary BM transplantation was comparable between Nox4 deficient and WT mice. In addition, the frequency of colony forming cells in the BM under steady-state conditions did not differ between both mouse groups. However, Nox4 deficient mice possess more functional HSCs as observed in in vivo competitive repopulating unit (CRU) assays. Lin- cells derived from Nox4 knock out (KO) mice showed an increased CRU frequency and superior multilineage engraftment upon secondary transplantation. Surprisingly, ROS levels in different HSPC subsets of NOX4 KO mice were comparable to WT cells, implying that the absence of Nox4 in HSCs does not have a major intrinsic impact on HSC physiology via ROS. Therefore, the increased levels of functional HSCs observed in our studies may suggest a contribution of the BM microenvironment to steady-state hematopoiesis in the BM of Nox4 KO animals. Recent observations suggest a regulation of the BM stem cell pool by BM endothelial cells, in particular by the permeability state of the blood-bone marrow-barrier (Itkin T et al., ASH Annual Meeting Abstracts, 2012). Endothelial cells interact with HSCs predominantly via paracrine effects and control stem cell retention, egress and homing as well as stem cell activation. As Nox4 is highly expressed in endothelial cells and is involved in angiogenesis, we reasoned that the absence of NOX4 could affect HSC homeostasis through altered BM endothelium properties and barrier permeability state. Indeed, in preliminary assays we found reduced short-term homing of BM mononuclear cells into the BM of Nox4 deficient mice as compared to wild type hosts. Furthermore, in vivo administration of Evans Blue dye revealed reduced dye penetration into Nox4-/- BM compared to wild type mice upon intravenous injection. Taken together, these data indicate a reduced endothelial permeability in Nox4 KO mice. Ongoing experiments aim at further characterization of the Nox4-/- phenotype in BM sinusoidal and arteriolar endothelial cells, the impact of Nox4 deletion on BM hematopoietic and mesenchymal stem cells, and in deciphering the role of Nox4 in the bone marrow microenvironment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

2016 ◽  
Vol 62 ◽  
pp. 1-10 ◽  
Author(s):  
Ariane Scoumanne ◽  
Patricia Molina-Ortiz ◽  
Daniel Monteyne ◽  
David Perez-Morga ◽  
Christophe Erneux ◽  
...  
Keyword(s):  
Wild Type ◽  
Specific Expression ◽  
Knock Out ◽  
Kinase C ◽  
Inositol 1,4,5 Trisphosphate ◽  
Knock Out Mice ◽  
And Function

scholarly journals Vascular Endothelial Growth Factor D Is Dispensable for Development of the Lymphatic System

2005 ◽  
Vol 25 (6) ◽  
pp. 2441-2449 ◽  
Author(s):  
Megan E. Baldwin ◽  
Michael M. Halford ◽  
Sally Roufail ◽  
Richard A. Williams ◽  
Margaret L. Hibbs ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Tissue Mass ◽  
And Function ◽  
Endothelial Growth Factor ◽  
Deficient Mice

ABSTRACT Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.

scholarly journals Orexin/Hypocretin and Histamine Cross-Talk on Hypothalamic Neuron Counts in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Chiara Berteotti ◽  
Viviana Lo Martire ◽  
Sara Alvente ◽  
Stefano Bastianini ◽  
Cristiano Bombardi ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Neuron Development ◽  
Wild Type ◽  
Hypothalamic Neurons ◽  
Neuron Number ◽  
Knock Out ◽  
Orexin Neuron ◽  
Knock Out Mice ◽  
Deficient Mice

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t-test, P = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t-test, P = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals.

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