Pleiotropic Effects of Simvastatin on the Regulation of Potassium Channels in Monocytes

Abstract

Purpose: The underlying mechanism of pleiotropic effects of statins on atherosclerosis is still unclear. Kv1.3 and KCa3.1 are two potassium channels that might be involved in monocyte migration and atherosclerosis formation. The aim of this study was to investigate the effect of simvastatin on the Kv1.3 and KCa3.1 in monocyte.Methods and Results: In human monocytic THP-1 cells, simvastatin significantly inhibited Kv1.3 mRNA and protein expression by real-time quantitative PCR analysis and western blotting. However, simvastatin had no effects on KCa3.1 mRNA and protein expression. By whole-cell patch clamp, simvastatin (10 mM) remarkably inhibited the current intensity of Kv1.3, but had no effect on KCa3.1. Simvastatin (10 mM) treatment significantly reduced the monocyte chemoattractant protein 1 (MCP-1)-induced monocyte migration. This inhibition was only partially reversed by mevalonate (1mM). In human peripheral blood mononuclear cells (PBMCs), both Kv1.3 and KCa3.1 mRNA expression were increased in patients with coronary artery diseases (CAD) (n = 20) compared to healthy controls (n = 22). However, simvastatin (40 mg per day) significantly inhibited the Kv1.3 but not KCa3.1 mRNA expression after 1 month and 3 months therapy in CAD patients. Conclusion:Our data suggested Kv1.3 in monocytes was a potential molecular target of the pleiotropic effects of statins. KCa3.1 might be another marker of CAD, but not associated with statins treatment.

Statins as inhibitors of voltage-gated potassium channels Kv1.3 in cancer cells

“…A more detailed study performed with lovastatin showed that this compound inhibits Kv1.3 channels expressed both in normal human T lymphocytes and in cancer cells of human Jurkat T cell line [17] . Studies performed recently by Wang and co-workers have shown that simvastatin inhibits Kv1.3 channels in human monocytic leukaemia THP-1 cells in a concentration-dependent manner [18] . However, these studies were performed applying a voltage step protocol, in which the membrane voltage is changed in a stepwise manner [ 18 ].…”

“…Studies performed recently by Wang and co-workers have shown that simvastatin inhibits Kv1.3 channels in human monocytic leukaemia THP-1 cells in a concentration-dependent manner [18] . However, these studies were performed applying a voltage step protocol, in which the membrane voltage is changed in a stepwise manner [ 18 ]. This is in contrast to a gradual change of the voltage that occurs in case of the voltage ramp sequence applied in our studies (see below).…”

The role of potassium in atherosclerosis

“…This effect would rely on direct interactions with the channel protein: (a) modulation of channel gating and conformation due to changes in bilayer fluidity; (b) compartmentalization of ion channels into spatially restricted signalling complexes (lipid rafts) 57 . In line with a potential inhibitory effect on Kv1.3 RNA expression has been reported for simvastatin 58 . Although a clear mechanism has not yet been demonstrated for this effect, it may be ascribed to the pleiotropic effect of this class of drugs 59‐64 …”

“…57 In line with a potential inhibitory effect on Kv1.3 RNA expression has been reported for simvastatin. 58 Although a clear mechanism has not yet been demonstrated for this effect, it may be ascribed to the pleiotropic effect of this class of drugs. [59][60][61][62][63][64] Along with the growing body of such experimental evidence, the physiology of K + channel has advanced substantially in the recent years.…”

Review on Biological Characteristics of Kv1.3 and Its Role in Liver Diseases

“…Many studies have shown that besides being highly expressed in T lymphocytes, Kv1.3 is also expressed in other immune cells, including microglia, lymphocytes, and macrophages. Using an electrophysiological technique, characteristic currents of Kv1.3 were recorded in human bone marrow-derived macrophages, mammalian macrophages, microglia, monocytes, human alveolar macrophages, and other cells (Gallin, 1984;Mckinney and Gallin, 1990;Nelson et al, 1990;Kotecha and Schlichter, 1999;Cahalan et al, 2001;Mackenzie et al, 2003;Xie et al, 2015;Lowinus, 2020;Wang, 2020).…”