Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function

Abstract

Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognised "off-targets" for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolaemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells since mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca 2+ influx via opening of voltage-gated Ca 2+ channels (VGCCs).We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption and ATP-sensitive-K + -channel activity were monitored as markers of mETC activity, respiration and cellular ATP/ADP ratio respectively; Ca 2+ channel activity and Ca 2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 ~ 3 µM) and mETC (1< IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar's absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an "off target".

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

“…More recently, it has been suggested that statins can reduce the membrane potential by inhibiting mitochondrial complex II activity, which causes oxidative stress [74]. These off-target effects of statins have been very recently corroborated by Curry et al [75] in experiments showing that simvastatin impairs β-cell function by at least two mechanisms: (1) via direct inhibition of K ATP channels in a mitochondria-independent manner and (2) via interference with mitochondrial respiration, thus decreasing cytosolic ATP levels and inhibiting metabolic upregulation of L-type Ca 2+ channels [75].…”

Statin therapy associated with decreased neuronal injury measured by serum S100β levels in patients with acute ischemic stroke

“…Since, the release and action of S100β are calcium-dependent, mainly cytosolic ca + 2 , a recent work illustrated that simvastatin inhibits cytosolic ca + 2 in AIS, thereby may inhibits the release of S100β from ischemic neurons. [ 43 ] Indeed, statins inhibit acute activation of astrocyte cells in AIS, and other modalities of brain injury and prevent astrocyte cells for synthesis of new S100β. [ 44 ] These findings, might explain the low level of S100β in patients with AIS on statins therapy compared with nonstatins therapy.…”

Цукровий Діабет, Дисліпопротеїнемії Та Статини

“…Ймовірно, що інгібітори ГМГ-КоАредуктази здатні знижувати мембранний потенціал, пригнічувати активність мітохондріального комплексу II, що зумовлює ОС [45]. Ці нецільові ефекти інгібіторів ГМГ-КоАредуктази підтверджені експериментально, зокрема, показано, що симвастатин змінює функцію β-клітин, принаймні, через два механізми: (1) шляхом прямого інгібування АТФзалежних калієвих каналів і (2) шляхом втручання в мітохондріальне дихання -внаслідок зниження рівня цитозольного АТФ і пригнічення активності Са 2+ -каналів L-типу [46].…”