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, Jahrgang 8, Nr. 11, 2013, S. e81006.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -