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The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy

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The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy. / Chen, Yi-Je; Lam, Jenny; Gregory, Clare R; Schrepfer, Sonja; Wulff, Heike.

In: PLOS ONE, Vol. 8, No. 11, 2013, p. e81006.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Chen, Y-J, Lam, J, Gregory, CR, Schrepfer, S & Wulff, H 2013, 'The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy', PLOS ONE, vol. 8, no. 11, pp. e81006. https://doi.org/10.1371/journal.pone.0081006

APA

Chen, Y-J., Lam, J., Gregory, C. R., Schrepfer, S., & Wulff, H. (2013). The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy. PLOS ONE, 8(11), e81006. https://doi.org/10.1371/journal.pone.0081006

Vancouver

Chen Y-J, Lam J, Gregory CR, Schrepfer S, Wulff H. The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy. PLOS ONE. 2013;8(11):e81006. https://doi.org/10.1371/journal.pone.0081006

Bibtex

@article{1258a081212a4c73b69d35bd4cf65830,
title = "The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy",
abstract = "Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4(+) memory T cells. We here tested whether two experimental immunosuppressants targeting K(+) channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7(-) memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy. ",
keywords = "Allografts/blood supply, Aminopeptidases/metabolism, Animals, Collagen/metabolism, Gene Expression, Graft Rejection/metabolism, Humans, Interferon-gamma/blood, Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors, Kv1.3 Potassium Channel/genetics, Male, Organ Transplantation/adverse effects, Pancreatitis-Associated Proteins, Pyrazoles/pharmacology, Rats, Tunica Intima/metabolism, Vascular Diseases/etiology",
author = "Yi-Je Chen and Jenny Lam and Gregory, {Clare R} and Sonja Schrepfer and Heike Wulff",
year = "2013",
doi = "10.1371/journal.pone.0081006",
language = "English",
volume = "8",
pages = "e81006",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

RIS

TY - JOUR

T1 - The Ca²⁺-activated K⁺ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy

AU - Chen, Yi-Je

AU - Lam, Jenny

AU - Gregory, Clare R

AU - Schrepfer, Sonja

AU - Wulff, Heike

PY - 2013

Y1 - 2013

N2 - Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4(+) memory T cells. We here tested whether two experimental immunosuppressants targeting K(+) channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7(-) memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy.

AB - Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4(+) memory T cells. We here tested whether two experimental immunosuppressants targeting K(+) channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7(-) memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy.

KW - Allografts/blood supply

KW - Aminopeptidases/metabolism

KW - Animals

KW - Collagen/metabolism

KW - Gene Expression

KW - Graft Rejection/metabolism

KW - Humans

KW - Interferon-gamma/blood

KW - Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors

KW - Kv1.3 Potassium Channel/genetics

KW - Male

KW - Organ Transplantation/adverse effects

KW - Pancreatitis-Associated Proteins

KW - Pyrazoles/pharmacology

KW - Rats

KW - Tunica Intima/metabolism

KW - Vascular Diseases/etiology

U2 - 10.1371/journal.pone.0081006

DO - 10.1371/journal.pone.0081006

M3 - SCORING: Journal article

C2 - 24312257

VL - 8

SP - e81006

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 11

ER -