Article

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans.

Department of Medicine and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Journal of Clinical Investigation (impact factor: 15.39). 10/2008; 118(9):3025-37. DOI:10.1172/JCI30836
Source: PubMed

ABSTRACT 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.

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Keywords

aortas
 
Atherosclerosis
 
channel inhibits VSMC
 
coronary artery disease
 
decreasing infiltration
 
developed world
 
discernible toxicity
 
infiltrated atherosclerotic lesions
 
influenza virus
 
intermediate-conductance calcium-activated potassium channel KCa3.1
 
KCa3.1 blockers
 
KCa3.1 suppressed proliferation
 
lower cholesterol
 
multiple cell types
 
oxidative stress
 
promising therapeutic strategy
 
Selective pharmacological blockade
 
suppressing VSMC proliferation
 
Therapeutic concentrations
 
VSMC proliferation