Journal Article

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

Harder, David R., Fujiwara, Yoshimasa, Azam, Philippe, Saito, Takashi, Raman, Girija, Melvin, James E., Toyama, Kazuyoshi, Pratt, Phillip F., Hatoum, Ossama A., Wulff, Heike, Gutterman, David D., Miura, Hiroto, Mattson, David L., Das, Satarupa, Chandy, K. George

2008

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Aorta - metabolism / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - metabolism / Biomedical research / Cardiovascular disease / Care and treatment / Cell proliferation / Clotrimazole - pharmacology / Control / Coronary vessels / Cytochrome / Diagnosis / Genetic aspects / Humans / Intermediate-Conductance Calcium-Activated Potassium Channels - genetics / Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism / Lipids / Lymphocytes / Macrophages - metabolism / Mice / Mice, Transgenic / Models, Biological / Oxidative Stress / Physiological aspects / Potassium / Potassium channels / Pyrazoles - pharmacology / Risk factors / T-Lymphocytes - metabolism / Vein & artery diseases