The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans
Kazuyoshi Toyama, … , David R. Harder, Hiroto Miura
Kazuyoshi Toyama, … , David R. Harder, Hiroto Miura
Published August 7, 2008
Citation Information: J Clin Invest. 2008;118(9):3025-3037. https://doi.org/10.1172/JCI30836.
View: Text | PDF
Research Article Vascular biology

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

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.

Authors

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

×

Figure 9

Antiatherosclerotic effect of KCa3.1 blockade therapy with TRAM-34 in Apoe–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Antiatherosclerotic effect of KCa3.1 blockade therapy with TRAM-34 in Ap...
Typical atherosclerotic lesions in the aortic root of a mouse treated with vehicle (A–E) or TRAM-34 (F–J). Serial 5-μm sections were stained with Sudan III (A and F); Abs specific to VSMCs (α-SMA; B and G), macrophages (Mac3; C and H), or T cells (CD3; D and I); or H&E (E and J). (K) Left: Representative images comparing fluorescence intensity of dihydroethidine, representing the production of superoxide in isolated iliac arteries of Apoe–/– mice treated with vehicle or TRAM-34. Vessels with no intimal plaques were isolated, incubated with dihydroethidine, and laid on glass slides, and images were taken perpendicularly to vessels. Each vessel is traced with white dotted lines. Right: Summary of fluorescence intensities (normalized to vehicle-treated Apoe–/– mice) in 7 arteries of each group. Dihydroethidine fluorescence intensity was significantly decreased in TRAM-34–treated Apoe–/– mouse arteries. #P < 0.05 versus vehicle. Scale bars: 200 μm (A and F), 100 μm (B, C, E, G, H, J, and K), 50 μm (D and I).