The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans.
Atherosclerosis remains a major cause of death in the developed world despite the success of therapies that lower cholesterol and BP. The intermediate-conductance calcium-activated potassium channel KCa3.1 is expressed in multiple cell types implicated in atherogenesis, and pharmacological blockade of this channel inhibits VSMC and lymphocyte activation in rats and mice. We found that coronary vessels from patients with coronary artery disease expressed elevated levels of KCa3.1. In Apoe(-/-) mice, a genetic model of atherosclerosis, KCa3.1 expression was elevated in the VSMCs, macrophages, and T lymphocytes that infiltrated atherosclerotic lesions. Selective pharmacological blockade and gene silencing of KCa3.1 suppressed proliferation, migration, and oxidative stress of human VSMCs. Furthermore, VSMC proliferation and macrophage activation were reduced in KCa3.1(-/-) mice. In vivo therapy with 2 KCa3.1 blockers, TRAM-34 and clotrimazole, significantly reduced the development of atherosclerosis in aortas of Apoe(-/-) mice by suppressing VSMC proliferation and migration into plaques, decreasing infiltration of plaques by macrophages and T lymphocytes, and reducing oxidative stress. Therapeutic concentrations of TRAM-34 in mice caused no discernible toxicity after repeated dosing and did not compromise the immune response to influenza virus. These data suggest that KCa3.1 blockers represent a promising therapeutic strategy for atherosclerosis.
Toyama
Kazuyoshi
K
Department of Medicine and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Wulff
Heike
H
Chandy
K George
KG
Azam
Philippe
P
Raman
Girija
G
Saito
Takashi
T
Fujiwara
Yoshimasa
Y
Mattson
David L
DL
Das
Satarupa
S
Melvin
James E
JE
Pratt
Phillip F
PF
Hatoum
Ossama A
OA
Gutterman
David D
DD
Harder
David R
DR
Miura
Hiroto
H
D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D003022:Clotrimazole / Q000494:pharmacology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018384:Oxidative Stress; D011720:Pyrazoles / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; C411671:TRAM 34; D003022:Clotrimazole