Faculty Collaboration Database

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J Clin Invest 2008 Sep;118(9):3025-37

Date

08/09/2008

Pubmed ID

18688283

Pubmed Central ID

PMC2496961

DOI

10.1172/JCI30836

Scopus ID

2-s2.0-51349157566 (requires institutional sign-in at Scopus site)   192 Citations

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.

Author List

Toyama K, Wulff H, Chandy KG, Azam P, Raman G, Saito T, Fujiwara Y, Mattson DL, Das S, Melvin JE, Pratt PF, Hatoum OA, Gutterman DD, Harder DR, Miura H

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Atherosclerosis
Clotrimazole
Humans
Intermediate-Conductance Calcium-Activated Potassium Channels
Macrophages
Mice
Mice, Transgenic
Models, Biological
Oxidative Stress
Pyrazoles
T-Lymphocytes