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.

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…The SK4‐dependent current fraction (difference between red and black symbols in Fig. 1G) exhibited strong inward rectification as reported for canonical SK4 channels which are usually present at the plasma membrane of, for example, endothelial cells and smooth muscle cells (Grgic et al ., 2005; Toyama et al ., 2008). …”

“…Current knowledge suggests that BK (Lallet‐Daher et al ., 2009; Parihar et al ., 2003; Stegen et al ., 2015) and SK4 (Ouadid‐Ahidouch et al ., 2004; Parihar et al ., 2003; Steinle et al ., 2011) activities are required for malignant growth of several tumour‐derived cell lines and of xenografts in immunocompromised mice, highlighting a general role of K Ca channels for cell cycle‐specific functions (Huang and Jan, 2014; Pardo and Stuhmer, 2014). Expression of SK4 and BK in cancer cells follows a cell cycle‐dependent mode (Ouadid‐Ahidouch et al ., 2004; Pardo et al ., 1998) and the mitogen‐dependent regulation of K Ca activity supports a role for both channels in malignant (Faouzi et al ., 2010; Lallet‐Daher et al ., 2009; Wang et al ., 2007a) and nonmalignant cell proliferation (Grgic et al ., 2005; Khanna et al ., 1999; Toyama et al ., 2008; Yu et al ., 2013). By inducing a more negative membrane voltage, activation of K + channels provides a driving force for Ca 2+ influx into the nonexcitable tumour cell.…”

KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells

“…16 In cellcounting experiment, rat VSMCs were plated in 24-well plates at a density of 1 Â 10 5 cells per well (or 1 Â 10 4 cells per well in RNAi) in 1 ml DMEM containing 10% FBS. After starving for 24 h or 6 h (in RNAi) in DMEM containing 0.1% FBS, the cells were pretreated by K Ca 3.1 channel blocker or anti-RAGE antibody for 30 min, or K Ca 3.1 channel siRNA for 24 h before AGE-BSA was added.…”

“…15 Local delivery of TRAM-34 via balloon catheter prevents ion channel phenotype switching (K Ca 1.1 to K Ca 3.1) in VSMCs of coronary artery and reduces subsequent restenosis. 14 Moreover, Toyama et al 16 have provided the additional evidence that upregulation of K Ca 3.1 channels is related to atherogenesis in mice and humans.…”

Pharmacological gating modulation of small- and intermediate-conductance Ca2+-activated K+channels (KCa2.x and KCa3.1)

“…Furthermore, it has been observed that classical positive KCNN modulators like 1-EBIO, NS309, and SKA-31 can reduce the expression of K Ca 3.1 in proliferative vascular smooth muscle cells as well as K Ca 3.1 blockers or K Ca 3.1 silencing. 66,67 However, the phenomenon has not been reported for K Ca 2 channels in terminally differentiated cells like neurons and cardiomyocytes, and not described for K Ca 3.1 and K Ca 2.3 in vascular endothelium.…”