scholarly journals Pathway Analysis of a Transcriptome and Metabolite Profile to Elucidate a Compensatory Mechanism for Taurine Deficiency in the Heart of Taurine Transporter Knockout Mice

J ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 57-70
Author(s):  
Takashi Ito ◽  
Shigeru Murakami ◽  
Stephen Schaffer
Keyword(s):  
Pathway Analysis ◽  
Knockout Mice ◽  
Metabolite Profile ◽  
Integrated Analysis ◽  
Compensatory Mechanism ◽  
Compensatory Mechanisms ◽  
Taurine Transporter ◽  
Kegg Pathway Database ◽  
Taurine Deficiency ◽  
Pathway Analyses

Taurine, which is abundant in mammalian tissues, especially in the heart, is essential for cellular osmoregulation. We previously reported that taurine deficiency leads to changes in the levels of several metabolites, suggesting that alterations in those metabolites might compensate in part for tissue taurine loss, a process that would be important in maintaining cardiac homeostasis. In this study, we investigated the molecular basis for changes in the metabolite profile of a taurine-deficient heart using pathway analysis based on the transcriptome and metabolome profile in the hearts of taurine transporter knockout mice (TauTKO mice), which have been reported by us. First, the genes associated with transport activity, such as the solute carrier (SLC) family, are increased in TauTKO mice, while the established transporters for metabolites that are elevated in the TauTKO heart, such as betaine and carnitine, are not altered by taurine deficiency. Second, the integrated analysis using transcriptome and metabolome data revealed significant increases and/or decreases in the genes involved in Arginine metabolism, Ketone body degradation, Glycerophospholipid metabolism, and Fatty acid metabolism in the KEGG pathway database. In conclusion, these pathway analyses revealed genetic compensatory mechanisms involved in the control of the metabolome profile of the taurine-deficient heart.

PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation

2021 ◽  
Author(s):  
Zhenhua Li ◽  
Jingping Xu ◽  
Yao Song ◽  
Chong Xin ◽  
Lantao Liu ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Knockout Mice ◽  
Rna Splicing ◽  
Gene Knockout ◽  
Major Type ◽  
Integrated Analysis ◽  
Arginine Methyltransferase ◽  
Potential Strategy ◽  
Glcnac Transferase

Rationale: Protein O-GlcNAcylation is dynamically regulated by two key enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Excessive protein O-GlcNAcylation contributes to dilated cardiomyopathy (DCM), but its regulatory mechanisms are not fully understood. The protein arginine methyltransferase 5 (PRMT5) is the major type II arginine methyltransferase, which plays critical physiological roles by symmetrically dimethylating various downstream targets including proteins involved in RNA splicing. However, its function in regulating protein O-GlcNAcylation and DCM is unexplored. Objective: To elucidate the physiological function of PRMT5 and the mechanism underlying its role in regulating cardiac O-GlcNAcylation and homeostasis. Methods and Results: Conditional gene knockout was used to study the in vivo function of Prmt5 in regulating cardiac homeostasis. An integrated analysis of transcriptomic and metabolomic profiles was performed to investigate the molecular mechanism. Adeno-associated virus 9 (AAV9)-mediated gene delivery in the mouse was used to study the protein O-GlcNAcylation in Prmt5 deficiency-induced DCM. PRMT5 mRNA was decreased in human DCM hearts, and cardiomyocyte-specific Prmt5 deletion in mice resulted in DCM and heart failure. Transcriptomic and metabolomic profiling identified increased O-GlcNAcylation in the hearts of Prmt5-knockout mice. Mechanistically, Prmt5 deletion suppressed O-GlcNAcase (OGA) expression by inhibiting the transcription of Oga and triggering its aberrant splicing. Consistently, a positive correlation of PRMT5 and OGA was identified in human DCM hearts. Notably, gene therapy with AAV9 encoding the correctly spliced Oga normalized the cardiac protein O-GlcNAcylation levels and partially rescued the dilation and dysfunction of the hearts in Prmt5-knockout mice. Conclusions: Our data demonstrate a novel function of PRMT5 in regulating protein O-GlcNAcylation to maintain cardiac homeostasis, suggesting that targeting the PRMT5-OGA axis could be a potential strategy for treating DCM.

Cardiovascular and renal control in NOS-deficient mouse models

2003 ◽  
Vol 284 (3) ◽  
pp. R628-R638 ◽  
Author(s):  
Pablo A. Ortiz ◽  
Jeffrey L. Garvin
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Cardiac Function ◽  
Knockout Mice ◽  
Vascular Tone ◽  
Single Gene ◽  
No Production ◽  
Compensatory Mechanisms ◽  
Nos Isoforms ◽  
Regulation Of Vascular Tone

Nitric oxide (NO) plays an essential role in the maintenance of cardiovascular and renal homeostasis. Endogenous NO is produced by three different NO synthase (NOS) isoforms: endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). To investigate which NOS is responsible for NO production in different tissues, NOS knockout (−/−) mice have been generated for the three isoforms. This review focuses on the regulation of cardiovascular and renal function in relation to blood pressure homeostasis in the different NOS−/− mice. Although regulation of vascular tone and cardiac function in eNOS−/− has been extensively studied, far less is known about renal function in these mice. eNOS−/− mice are hypertensive, but the mechanism responsible for their high blood pressure is still not clear. Less is known about cardiovascular and renal control in nNOS−/− mice, probably because their blood pressure is normal. Recent data suggest that nNOS plays important roles in cardiac function, renal homeostasis, and regulation of vascular tone under certain conditions, but these are only now beginning to be studied. Inasmuch as iNOS is absent from the cardiovascular system under physiological conditions, it may become important to blood pressure regulation only during pathological conditions related to inflammatory processes. However, iNOS is constitutively expressed in the kidney, where its function is largely unknown. Overall, the study of NOS knockout mice has been very useful and produced many answers, but it has also raised new questions. The appearance of compensatory mechanisms suggests the importance of the different isoforms to specific processes, but it also complicates interpretation of the data. In addition, deletion of a single gene may have physiologically significant effects in addition to those being studied. Thus the presence or absence of a specific phenotype may not reflect the most important physiological function of the absent gene.

scholarly journals Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248964
Author(s):  
Jun-dae Kim ◽  
Lingping Zhu ◽  
Quan Sun ◽  
Longhou Fang
Keyword(s):  
Sexual Dimorphism ◽  
Knockout Mice ◽  
Metabolite Profiling ◽  
Krebs Cycle ◽  
Leigh Syndrome ◽  
Metabolite Profile ◽  
Cellular Functions ◽  
Metabolic Basis ◽  
And Control ◽  
Cellular Cholesterol Efflux

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.

scholarly journals Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†

2020 ◽  
Vol 103 (2) ◽  
pp. 357-367
Author(s):  
Erik B Faber ◽  
Nan Wang ◽  
Gunda I Georg
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Knockout Mice ◽  
Male Contraception ◽  
Cyclin Dependent Kinase ◽  
Compensatory Mechanisms ◽  
Binding Partner ◽  
Male Contraceptive ◽  
Clinical Stages

Abstract Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

A new compensatory mechanism for having only one feeding claw in male Uca rosea (Tweedie, 1937)

Crustaceana ◽  
2016 ◽  
Vol 89 (13) ◽  
pp. 1551-1558 ◽  
Author(s):  
Fahmida Wazed Tina ◽  
Mullica Jaroensutasinee ◽  
Krisanadej Jaroensutasinee
Keyword(s):  
Feeding Rate ◽  
Compensatory Mechanism ◽  
Fiddler Crabs ◽  
Compensatory Mechanisms

We investigated how male Uca rosea (Tweedie, 1937) have behaviourally or morphologically compensated for having only one functional feeding claw while females have two. We found that male U. rosea used four compensatory mechanisms: (1) larger feeding claws (dactyl length and width), (2) higher feeding rate/claw per min, (3) higher numbers of pinches/feeding claw per min than similar sized females, and (4) higher numbers of pinches/feeding claw lift than females of similar feeding rate/feeding claw per min. This study is the first one to demonstrate that taking higher numbers of pinches/feeding claw per min than comparable sized females, and taking higher numbers of pinches/feeding claw lift than females of similar feeding rate/claw per min are used as additional compensatory mechanisms for male fiddler crabs to compensate for having only one feeding claw.

scholarly journals Cardiac and skeletal muscle abnormality in taurine transporter-knockout mice

2010 ◽  
Vol 17 (Suppl 1) ◽  
pp. S20 ◽  
Author(s):  
Takashi Ito ◽  
Shohei Oishi ◽  
Mika Takai ◽  
Yasushi Kimura ◽  
Yoriko Uozumi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Taurine Transporter

scholarly journals Loss of Glyoxalase 1 Induces Compensatory Mechanism to Achieve Dicarbonyl Detoxification in Mammalian Schwann Cells

2016 ◽  
Vol 292 (8) ◽  
pp. 3224-3238 ◽  
Author(s):  
Jakob Morgenstern ◽  
Thomas Fleming ◽  
Dagmar Schumacher ◽  
Volker Eckstein ◽  
Marc Freichel ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Aldose Reductase ◽  
Mammalian Cells ◽  
Clinical Importance ◽  
Catalytic Efficiency ◽  
Compensatory Mechanism ◽  
Glyoxalase System ◽  
Compensatory Mechanisms ◽  
Knock Out ◽  
Glyoxalase 1

The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock-out model (GLO1−/−) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1−/− cells. Alternative detoxification of MG in GLO1−/− is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused by S-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1−/− cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG.

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2

2015 ◽  
Vol 309 (3) ◽  
pp. H481-H489 ◽  
Author(s):  
Søren Grubb ◽  
Gary L. Aistrup ◽  
Jussi T. Koivumäki ◽  
Tobias Speerschneider ◽  
Lisa A. Gottlieb ◽  
...  
Keyword(s):  
Action Potentials ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Cardiac Contraction ◽  
Compensatory Mechanism ◽  
Wild Type ◽  
Compensatory Mechanisms ◽  
Interacting Protein ◽  
Protein Levels ◽  
Cardiac Contractile

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K+ current ( Ito,f) and with CaV1.2 to mediate the inward L-type Ca2+ current ( ICa,L). Anesthetized KChIP2−/− mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca2+ entry into the cell, thereby augmenting Ca2+-induced Ca2+ release. Ca2+ transients in disaggregated KChIP2−/− cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca2+-induced Ca2+ release event. We next functionally probed dyad structure, ryanodine receptor Ca2+ sensitivity, and sarcoplasmic reticulum Ca2+ load and found that increased temporal synchronicity of the Ca2+ release in KChIP2−/− cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2−/− mice.

scholarly journals Light deprivation slows but does not prevent the loss of photoreceptors in taurine transporter knockout mice

2004 ◽  
Vol 44 (17) ◽  
pp. 2091-2100 ◽  
Author(s):  
K. Rascher ◽  
G. Servos ◽  
G. Berthold ◽  
H.-G. Hartwig ◽  
U. Warskulat ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Light Deprivation ◽  
Taurine Transporter

scholarly journals Protection of the Villus Epithelial Cells of the Small Intestine from Rotavirus Infection Does Not Require Immunoglobulin A

2000 ◽  
Vol 74 (9) ◽  
pp. 4102-4109 ◽  
Author(s):  
Christine M. O'Neal ◽  
Gregory R. Harriman ◽  
Margaret E. Conner
Keyword(s):  
T Cells ◽  
Normal Control ◽  
Knockout Mice ◽  
Immunoglobulin A ◽  
Primary Immune Response ◽  
Secretory Iga ◽  
Compensatory Mechanisms ◽  
Rotavirus Infection ◽  
Serum Iga ◽  
Mucosal Pathogens

ABSTRACT Immunoglobulin A (IgA) is the primary immune response induced in the intestine by rotavirus infection, but vaccination with virus-like particles induces predominantly IgG, not IgA. To definitively assess the role of IgA in protection from rotavirus infection, IgA knockout mice, which are devoid of serum and secretory IgA, were infected and then rechallenged with murine rotavirus at either 6 weeks or 10 months. Following primary rotavirus infection, IgA knockout mice cleared virus as effectively as IgA normal control mice. Rotavirus-infected IgA knockout mice produced no serum or fecal IgA but did have high levels of antirotavirus serum IgG and IgM and fecal IgG, whereas IgA normal control mice made both serum IgA and IgG and fecal IgA. Both IgA normal and IgA knockout mice were totally protected from rotavirus challenge at 42 days. Ten months following a primary infection, both IgA normal and knockout mice still had high levels of serum and fecal antirotavirus antibody and were totally protected from rotavirus challenge. To determine if compensatory mechanisms other than IgG were responsible for protection from rotavirus infection in IgA knockout mice, mice were depleted of CD4+ T cells or CD8+ T cells. No changes in the level of protection were seen in depleted mice. These data show that fecal or systemic IgA is not essential for protection from rotavirus infection and suggest that in the absence of IgA, IgG may play a significant role in protection from mucosal pathogens.

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