Abstract 20036: Genetic Disruption of KCa3.1 Suppresses the Development of Atherosclerosis
Aim We previously reported that the expression and activity of intermediate-conductance calcium-activated potassium channels encoded by the KCa3.1 gene are elevated in macrophages (MØ), smooth muscle cells (SMCs) and T cells that infiltrated atherosclerotic plaques in mice and humans and that in-vivo therapy with the channel blockers suppresses the plaque formation in apoE−/− mice by inhibiting activations of these cell types. Here we examined the precise role of KCa3.1 gene in atherogenesis.
Methods: ApoE−/− mice bearing a combination of KCa3.1+/+ and −/− were generated by crossing apoE−/− mice with KCa3.1−/− mice. En face analysis of atherosclerotic lesions in aortic trees and carotid arteries and quantitative analysis of histological characteristics in the plaques of aortic sinus were performed using Sudan III and cell specific antibodies. Proliferatory responses to granulocyte/macrophage colony-stimulating factor (CSF, 10 ng/ml) and superoxide production, as visualized by dihydroethidine-dependent fluorescence, were examined in peritoneal MØ from KCa3.1+/+ and −/− mice.
Results: Quantitative measurements of atherosclerotic lesion area demonstrated that apoE−/−KCa3.1+/+ mice developed extensive lesions in aortic trees and in carotid arteries (aortas: 1±1, 6±2 and 15±3%, and carotid; 4±2, 5±2 and 16±5% at 10, 16 and 24 weeks of age, n=5–9). Histological analysis of aortic sinus revealed a significant infiltration of plaques by MØ in apoE−/−KCa3.1+/+ mice (% of plaque area; MØ 46±3, p<0.05 vs. SMC 25±3 and necrosis 14±3%, n=9). ApoE−/−KCa3.1−/− mice showed statistically significant reductions in the lesion area, both in aortas and in carotid arteries (aortas: 0.1±0.1, 2±0.2 and 4±0.4% and carotid; 0.3±0.1, 2±1 and 2±1%, n=8–13, p<0.05 vs. apoE−/−KCa3.1+/+ mice, respectively). Proliferatory response of KCa3.1−/− MØ to CSF was significantly smaller than KCa3.1+/+ MØ (KCa3.1−/− 2.2±0.6 fold of control, p<0.05 vs. KCa3.1+/+ 3.9±0.6, n=10–11). Moreover, KCa3.1−/− significantly reduced superoxide production in MØ.
Conclusions: KCa3.1 deficiency suppresses the development of atherosclerosis in apoE−/− mice by markedly inhibiting macrophage activations. KCa3.1 is a novel therapeutic target for the prevention of atherosclerosis.
- © 2010 by American Heart Association, Inc.