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.
authors: Department of Pharmacology, University of California, Davis, California, United States of America.
authors: Yi-Je
authors: YJ
authors: Chen
authors: Jenny
authors: J
authors: Lam
authors: Clare R
authors: CR
authors: Gregory
authors: Sonja
authors: S
authors: Schrepfer
authors: Heike
authors: H
authors: Wulff
mesh_terms: D064591:Allografts / Q000098:blood supply / Q000473:pathology*; D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D016377:Organ Transplantation / Q000009:adverse effects*; D000073718:Pancreatitis-Associated Proteins; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D014652:Vascular Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D011720:Pyrazoles; C000612141:REG3A protein, human; C411671:TRAM 34; D007371:Interferon-gamma; D003094:Collagen; D000626:Aminopeptidases