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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3025-3037
Number of pages13
JournalJournal of Clinical Investigation
Volume118
Issue number9
DOIs
StatePublished - Sep 2 2008
Externally publishedYes

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Intermediate-Conductance Calcium-Activated Potassium Channels
Atherosclerosis
Apolipoproteins E
Oxidative Stress
Macrophages
Pharmacology
Clotrimazole
T-Lymphocytes
Macrophage Activation
Genetic Models
Gene Silencing
Therapeutics
Lymphocyte Activation
Orthomyxoviridae
Aorta
Coronary Artery Disease
Cause of Death
Coronary Vessels
Cholesterol

ASJC Scopus subject areas

  • Medicine(all)

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The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. / Toyama, Kazuyoshi; Wulff, Heike; Chandy, K. George; Azam, Philippe; Raman, Girija; Saito, Takashi; Fujiwara, Yoshimasa; Mattson, David L.; Das, Satarupa; Melvin, James E.; Pratt, Phillip F.; Hatoum, Ossama A.; Gutterman, David D.; Harder, David R.; Miura, Hiroto.

In: Journal of Clinical Investigation, Vol. 118, No. 9, 02.09.2008, p. 3025-3037.

Research output: Contribution to journalArticle

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 2008, 'The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans', Journal of Clinical Investigation, vol. 118, no. 9, pp. 3025-3037. https://doi.org/10.1172/JCI30836
Toyama, Kazuyoshi ; Wulff, Heike ; Chandy, K. George ; Azam, Philippe ; Raman, Girija ; Saito, Takashi ; Fujiwara, Yoshimasa ; Mattson, David L. ; Das, Satarupa ; Melvin, James E. ; Pratt, Phillip F. ; Hatoum, Ossama A. ; Gutterman, David D. ; Harder, David R. ; Miura, Hiroto. / The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 9. pp. 3025-3037.
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