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Article ; Online: Prevention and Reversal of Frailty in Heart Failure　- A Systematic Review.

Aili, Samira R / Lo, Phillip / Villanueva, Jeanette E / Joshi, Yashutosh / Emmanuel, Sam / Macdonald, Peter S

Circulation journal : official journal of the Japanese Circulation Society

2021 Volume 86, Issue 1, Page(s) 14–22

Abstract: Background: Frailty is prevalent in patients with heart failure (HF) and associated with increased morbidity and mortality. Hence, there has been increased interest in the reversibility of frailty following treatment with medication or surgery. This ... ...

Abstract	Background: Frailty is prevalent in patients with heart failure (HF) and associated with increased morbidity and mortality. Hence, there has been increased interest in the reversibility of frailty following treatment with medication or surgery. This systematic review aimed to assess the reversibility of frailty in patients with HF before and after surgical interventions aimed at treating the underlying cause of HF. It also aimed to assess the efficacy of cardiac rehabilitation and prehabilitation in reversing or preventing frailty in patients with HF.Methods and Results:Searches of PubMed, MEDLINE and Academic Search Ultimate identified studies with HF patients undergoing interventions to reverse frailty. Titles, abstracts and full texts were screened for eligibility based on the PRISMA guidelines and using predefined inclusion/exclusion criteria in relation to participants, intervention, control, outcome and study design. In total, 14 studies were included: 3 assessed the effect of surgery, 7 assessed the effect of rehabilitation programs, 2 assessed the effect of a prehabilitation program and 2 assessed the effect of program interruptions on HF patients. Conclusions: Overall, it was found that frailty is at least partially reversible and potentially preventable in patients with HF. Interruption of rehabilitation programs resulted in deterioration of the frailty status. Future research should focus on the role of prehabilitation in mitigating frailty prior to surgical intervention.
MeSH term(s)	Cardiac Rehabilitation/methods ; Frailty ; Heart Failure/complications ; Heart Failure/prevention & control ; Humans
Language	English
Publishing date	2021-10-27
Publishing country	Japan
Document type	Journal Article ; Systematic Review
ZDB-ID	2068090-9
ISSN	1347-4820 ; 1346-9843
ISSN (online)	1347-4820
ISSN	1346-9843
DOI	10.1253/circj.CJ-21-0819
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Article ; Online: The cardioprotective potential of the sodium-glucose cotransporter 2 inhibitor empagliflozin in donor heart preservation.

Villanueva, Jeanette E / Gao, Ling / Doyle, Aoife / Scheuer, Sarah E / Hicks, Mark / Jabbour, Andrew / Macdonald, Peter S

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

2020 Volume 39, Issue 10, Page(s) 1151–1153

MeSH term(s)	Animals ; Benzhydryl Compounds/pharmacology ; Disease Models, Animal ; Glucosides/pharmacology ; Heart Transplantation/methods ; Organ Preservation/methods ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Tissue Donors
Chemical Substances	Benzhydryl Compounds ; Glucosides ; Sodium-Glucose Transporter 2 Inhibitors ; empagliflozin (HDC1R2M35U)
Language	English
Publishing date	2020-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1062522-7
ISSN	1557-3117 ; 1053-2498
ISSN (online)	1557-3117
ISSN	1053-2498
DOI	10.1016/j.healun.2020.06.007
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Article: The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death.

Villanueva, Jeanette E / Chew, Hong C / Gao, Ling / Doyle, Aoife / Scheuer, Sarah E / Hicks, Mark / Jabbour, Andrew / Dhital, Kumud K / Macdonald, Peter S

Transplantation direct

2021 Volume 7, Issue 6, Page(s) e699

Abstract: Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates ... ...

Abstract	Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation. Methods: Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity. Results: Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage. Conclusions: Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.
Language	English
Publishing date	2021-05-18
Publishing country	United States
Document type	Journal Article
ISSN	2373-8731
ISSN	2373-8731
DOI	10.1097/TXD.0000000000001148
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Article ; Online: Cyclosporine A as a Cardioprotective Agent During Donor Heart Retrieval, Storage, or Transportation: Benefits and Limitations.

Gao, Ling / Hicks, Mark / Villanueva, Jeanette E / Doyle, Aoife / Chew, Hong C / Qui, Min Ru / Jabbour, Andrew / Dhital, Kumud K / Macdonald, Peter S

Transplantation

2019 Volume 103, Issue 6, Page(s) 1140–1151

Abstract: Background: Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and ... ...

Abstract	Background: Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and duration of cardiac exposure to cyclosporine A (CsA), another putative mitochondrial protectant, on cardiac functional recovery and potential mechanisms of CsA action in an isolated working rat heart model of donor heart retrieval and storage. Methods: After measurement of baseline function, hearts were arrested and stored for 6 hours at 4°C in either Celsior alone or Celsior + CsA (0.2 µM), then reperfused for 45 minutes in Krebs solution, when functional recovery was assessed. Two additional groups of Celsior-alone stored hearts were exposed to 0.2 µM CsA for the initial 15 minutes (nonworking period) or the full 45-minute period of reperfusion. Coronary effluent was collected pre- and poststorage for assessment of lactate dehydrogenase release. Tissue samples were collected at the end of each study for immunoblotting and histological studies. Results: CsA supplementation during cold storage or the first 15-minute reperfusion significantly improved functional recovery and significantly increased phospho-AMPKαThr172 and phospho-ULK-1Ser757. Hearts exposed to CsA for 45 minutes at reperfusion recovered poorly with no phospho-AMP-activated protein kinase α activation, decreased phospho-eNOSSer633, and decreased mitochondrial cytochrome c content with increased lactate dehydrogenase release. Conclusions: Inclusion of CsA during cold storage is cardioprotective. Effects of CsA addition to the perfusate during reperfusion were time dependent, with benefits at 15 minutes but not 45 minutes of reperfusion. The toxic effect with the presence of CsA for the full 45-minute reperfusion is associated with impaired mitochondrial integrity and decreased eNOS phosphorylation.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Animals ; Autophagy-Related Protein-1 Homolog/metabolism ; Cardioplegic Solutions/pharmacology ; Cardioplegic Solutions/toxicity ; Cold Ischemia ; Cyclosporine/pharmacology ; Cyclosporine/toxicity ; Disaccharides/pharmacology ; Disaccharides/toxicity ; Electrolytes/pharmacology ; Electrolytes/toxicity ; Glutamates/pharmacology ; Glutamates/toxicity ; Glutathione/pharmacology ; Glutathione/toxicity ; Heart/drug effects ; Heart/physiopathology ; Heart Transplantation/adverse effects ; Histidine/pharmacology ; Histidine/toxicity ; Isolated Heart Preparation ; Male ; Mannitol/pharmacology ; Mannitol/toxicity ; Mitochondria, Heart/drug effects ; Mitochondria, Heart/metabolism ; Mitochondria, Heart/pathology ; Nitric Oxide Synthase Type III/metabolism ; Organ Preservation ; Organ Preservation Solutions/pharmacology ; Organ Preservation Solutions/toxicity ; Phosphorylation ; Rats, Wistar ; Recovery of Function ; Time Factors
Chemical Substances	Cardioplegic Solutions ; Celsior ; Disaccharides ; Electrolytes ; Glutamates ; Organ Preservation Solutions ; Mannitol (3OWL53L36A) ; Histidine (4QD397987E) ; Cyclosporine (83HN0GTJ6D) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Nos3 protein, rat (EC 1.14.13.39) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; ULK1 protein, rat (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2019-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000002629
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Zs.A 488: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 509: Show issues

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Article ; Online: Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model.

Villanueva, Jeanette E / Gao, Ling / Chew, Hong C / Hicks, Mark / Doyle, Aoife / Qui, Min Ru / Dhital, Kumud K / Macdonald, Peter S / Jabbour, Andrew

PloS one

2018 Volume 13, Issue 10, Page(s) e0205850

Abstract: The ryanodine receptor antagonist dantrolene inhibits calcium release from the sarcoplasmic reticulum and reduces cardiac ischaemia-reperfusion injury (IRI) in global warm ischaemia models however the cardioprotective potential of dantrolene under ... ...

Abstract	The ryanodine receptor antagonist dantrolene inhibits calcium release from the sarcoplasmic reticulum and reduces cardiac ischaemia-reperfusion injury (IRI) in global warm ischaemia models however the cardioprotective potential of dantrolene under hypothermic conditions is unknown. This study addresses whether the addition of dantrolene during cardioplegia and hypothermic storage of the donor heart can improve functional recovery and reduce IRI. Using an ex vivo isolated working heart model, Wistar rat (3 month and 12 month) hearts were perfused to acquire baseline haemodynamic measurements of aortic flow, coronary flow, cardiac output, pulse pressure and heart rate. Hearts were arrested and stored in Celsior preservation solution supplemented with 0.2-40 μM dantrolene for 6 hours at 4°C, then reperfused (15 min Langendorff, 30 min working mode). In 3-month hearts, supplementation with 1 μM dantrolene significantly improved aortic flow and cardiac output compared to unsupplemented controls however lactate dehydrogenase (LDH) release and contraction bands were comparable. In contrast, 40 μM dantrolene-supplementation yielded poor cardiac recovery, increased post-reperfusion LDH but reduced contraction bands. All 3-month hearts stored in dantrolene displayed significantly reduced cleaved-caspase 3 intensities compared to controls. Analysis of cardioprotective signalling pathways showed no changes in AMPKα however dantrolene increased STAT3 and ERK1/2 signaling in a manner unrelated to functional recovery and AKT activity was reduced in 1 μM dantrolene-stored hearts. In contrast to 3-month hearts, no significant improvements were observed in the functional recovery of 12-month hearts following prolonged storage in 1 μM dantrolene. Conclusions: Dantrolene supplementation at 1 μM during hypothermic heart preservation improved functional recovery of young, but not older (12 month) hearts. Although the molecular mechanisms responsible for dantrolene-mediated cardioprotection are unclear, our studies show no correlation between improved functional recovery and SAFE and RISK pathway activation.
MeSH term(s)	Animals ; Cold Temperature ; Cryopreservation ; Dantrolene/pharmacology ; Dietary Supplements ; Heart/drug effects ; Heart/physiology ; Hemodynamics ; In Vitro Techniques ; Male ; Organ Preservation ; Organ Preservation Solutions ; Rats ; Rats, Wistar ; Reperfusion Injury/prevention & control ; Signal Transduction
Chemical Substances	Organ Preservation Solutions ; Dantrolene (F64QU97QCR)
Language	English
Publishing date	2018-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0205850
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Article ; Online: TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15.

Villanueva, Jeanette E / Malle, Elisabeth K / Gardam, Sandra / Silveira, Pablo A / Zammit, Nathan W / Walters, Stacey N / Brink, Robert / Grey, Shane T

European journal of immunology

2015 Volume 45, Issue 6, Page(s) 1820–1831

Abstract: In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector ... ...

Abstract	In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/physiology ; Cellular Microenvironment ; Cytokines/pharmacology ; Female ; Gene Expression ; Homeostasis ; Immunologic Memory ; Immunophenotyping ; Interleukin-15/pharmacology ; Lymphocyte Count ; Lymphopenia/genetics ; Lymphopenia/immunology ; Lymphopenia/metabolism ; Male ; Mice ; Mice, Knockout ; NF-kappa B/metabolism ; Natural Killer T-Cells/drug effects ; Natural Killer T-Cells/physiology ; Phenotype ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Interleukin-15/genetics ; Receptors, Interleukin-15/metabolism ; Signal Transduction ; T-Lymphocyte Subsets/drug effects ; T-Lymphocyte Subsets/physiology ; TNF Receptor-Associated Factor 2/genetics ; TNF Receptor-Associated Factor 2/metabolism ; TNF Receptor-Associated Factor 3/genetics ; TNF Receptor-Associated Factor 3/metabolism
Chemical Substances	Cytokines ; Interleukin-15 ; NF-kappa B ; Receptors, Interleukin-15 ; TNF Receptor-Associated Factor 2 ; TNF Receptor-Associated Factor 3 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2015-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201445416
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice.

Mariño, Eliana / Walters, Stacey N / Villanueva, Jeanette E / Richards, James L / Mackay, Charles R / Grey, Shane T

European journal of immunology

2014 Volume 44, Issue 4, Page(s) 983–993

Abstract: Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability ... ...

Abstract	Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
MeSH term(s)	Animals ; Autoimmunity/genetics ; Autoimmunity/immunology ; B-Cell Activating Factor/genetics ; B-Cell Activating Factor/immunology ; B-Cell Activating Factor/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Proliferation ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/metabolism ; Female ; Flow Cytometry ; Glucose-6-Phosphatase/immunology ; Glucose-6-Phosphatase/metabolism ; Graft Rejection/genetics ; Graft Rejection/immunology ; Graft Survival/genetics ; Graft Survival/immunology ; Immunophenotyping ; Islets of Langerhans Transplantation/methods ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Time Factors
Chemical Substances	B-Cell Activating Factor ; Tnfsf13b protein, mouse ; Glucose-6-Phosphatase (EC 3.1.3.9) ; G6pc2 protein, mouse (EC 3.1.3.9.)
Language	English
Publishing date	2014-04
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201344186
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice.

Villanueva, Jeanette E / Walters, Stacey N / Saito, Mitsuru / Malle, Elisabeth K / Zammit, Nathan W / Watson, Katherine A / Brink, Robert / La Gruta, Nicole L / Alexander, Stephen I / Grey, Shane T

Diabetologia

2017 Volume 60, Issue 4, Page(s) 679–689

Abstract: Aims/hypothesis: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was ... ...

Abstract	Aims/hypothesis: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was associated with thromboembolic complications. Targeting downstream intracellular components shared between CD40 and other TNF family co-stimulatory molecules could bypass these complications. TNF receptor associated factor 2 (TRAF2) integrates multiple TNF receptor family signalling pathways that are critical for T cell activation and may be a central node of alloimmune responses. Methods: T cell-specific Traf2-deficient mice (Traf2TKO) were generated to define the role of TRAF2 in CD4 Results: Traf2TKO mice exhibited permanent survival of full MHC-mismatched pancreatic islet allografts without exogenous immunosuppression. Traf2TKO CD4 Conclusion/interpretation: Targeting TRAF2 may be useful as a therapeutic approach for immunosuppression-free islet allograft survival that avoids the thromboembolic complications associated with the use of anti-CD40L antibodies.
MeSH term(s)	Animals ; Blotting, Western ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Cell Proliferation/genetics ; Cell Proliferation/physiology ; Female ; Flow Cytometry ; Immunosuppression ; Islets of Langerhans Transplantation/immunology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; TNF Receptor-Associated Factor 2/genetics ; TNF Receptor-Associated Factor 2/metabolism ; Transplantation, Homologous
Chemical Substances	TNF Receptor-Associated Factor 2 ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2017-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-016-4198-7
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Article ; Online: Low-dose rapamycin unmasks the protective potential of targeting intragraft NF-κB for islet transplants.

Zammit, Nathan W / Tan, Bernice M / Walters, Stacey N / Liuwantara, David / Villanueva, Jeanette E / Malle, Elisabeth K / Grey, Shane T

Cell transplantation

2013 Volume 22, Issue 12, Page(s) 2355–2366

Abstract: Islet grafts can contribute to their own destruction via the elaboration of proinflammatory genes, many of which are transcriptionally regulated by nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB). Thus, NF-κB constitutes an enticing ... ...

Abstract	Islet grafts can contribute to their own destruction via the elaboration of proinflammatory genes, many of which are transcriptionally regulated by nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB). Thus, NF-κB constitutes an enticing gene therapy candidate to improve the success of islet transplantation. To test this hypothesis in vivo, we blocked NF-κB in BALB/c (H2(d)) to C57/BL6 (H2(b)) mouse islet allografts by genetically engineering islets to express the NF-κB superrepressor, IκBα. Here we show by microarray and RTqPCR that islets exhibit an intrinsic early immediate proinflammatory response, with the most highly upregulated proinflammatory genes comprising the chemokines Cxcl1, Cxcl2, Cxcl10, and Ccl2; the cytokines Tnf-α and Il-6; and the adhesion molecule Icam1. Overexpression of IκBα inhibited the expression of these genes by 50-95% in islets and MIN6 β-cells in vitro, by inhibiting NF-κB-dependent gene transcription. Histological and RTqPCR analysis at postoperative day (POD) 10 revealed that IκBα-transduced islet allografts exhibited improved islet architecture and strong insulin-labeling with decreased Ccl2 and Il-6 mRNA levels compared to the GFP-transduced control grafts. Despite these protective effects, NF-κB-blocked islet allografts were promptly rejected in our MHC-mismatched mouse model. However, IκBα-expressing grafts did harbor localized "pockets" of Foxp3(+) mononuclear cells not evident in the control grafts. This result suggested that the effect of the NF-κB blockade might synergize with regulatory T-cell-sparing rapamycin. Indeed, combining intragraft IκBα expression with low-dose rapamycin increased the mean survival time of islet allografts from 20 to 81 days, with 20% of the grafts surviving for greater than 100 days. In conclusion, rapamycin unmasks the protective potential of intragraft NF-κB blockade, which can, in some cases, permit permanent allograft survival without continuous systemic immunosuppression.
MeSH term(s)	Animals ; Cells, Cultured ; Chemokines/genetics ; Chemokines/metabolism ; Diabetes Mellitus, Experimental/mortality ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Experimental/surgery ; Drug Synergism ; Graft Survival/drug effects ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Immunosuppressive Agents/pharmacology ; Intercellular Adhesion Molecule-1/genetics ; Intercellular Adhesion Molecule-1/metabolism ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/metabolism ; Islets of Langerhans Transplantation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/metabolism ; Sirolimus/pharmacology ; Swine ; Transplantation, Homologous ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Chemokines ; Icam1 protein, mouse ; Immunosuppressive Agents ; Interleukin-6 ; NF-kappa B ; Tumor Necrosis Factor-alpha ; Intercellular Adhesion Molecule-1 (126547-89-5) ; I-kappa B Kinase (EC 2.7.11.10) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1135816-6
ISSN	1555-3892 ; 0963-6897
ISSN (online)	1555-3892
ISSN	0963-6897
DOI	10.3727/096368912X658737
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Article ; Online: Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Redd, Meredith A / Scheuer, Sarah E / Saez, Natalie J / Yoshikawa, Yusuke / Chiu, Han Sheng / Gao, Ling / Hicks, Mark / Villanueva, Jeanette E / Joshi, Yashutosh / Chow, Chun Yuen / Cuellar-Partida, Gabriel / Peart, Jason N / See Hoe, Louise E / Chen, Xiaoli / Sun, Yuliangzi / Suen, Jacky Y / Hatch, Robert J / Rollo, Ben / Xia, Di /

Alzubaidi, Mubarak A H / Maljevic, Snezana / Quaife-Ryan, Gregory A / Hudson, James E / Porrello, Enzo R / White, Melanie Y / Cordwell, Stuart J / Fraser, John F / Petrou, Steven / Reichelt, Melissa E / Thomas, Walter G / King, Glenn F / Macdonald, Peter S / Palpant, Nathan J

Circulation

2021 Volume 144, Issue 12, Page(s) 947–960

Abstract: Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular ... ...

Abstract	Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. Methods: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Results: Analysis of human complex trait genetics indicates that variants in the Conclusions: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
MeSH term(s)	Acid Sensing Ion Channels/biosynthesis ; Acid Sensing Ion Channels/genetics ; Animals ; Cells, Cultured ; Female ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/metabolism ; Isolated Heart Preparation/methods ; Male ; Mice ; Mice, Knockout ; Myocardial Ischemia/genetics ; Myocardial Ischemia/metabolism ; Myocardial Ischemia/therapy ; Myocardial Reperfusion Injury/genetics ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/therapy ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Polymorphism, Single Nucleotide/physiology ; Recovery of Function/drug effects ; Recovery of Function/physiology ; Spider Venoms/pharmacology
Chemical Substances	ASIC1 protein, human ; Acid Sensing Ion Channels ; Spider Venoms
Language	English
Publishing date	2021-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.121.054360
Database	MEDical Literature Analysis and Retrieval System OnLINE

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