The role of the mitochondria in apoptosis induced by 7β-hydroxycholesterol and cholesterol-5β,6β-epoxide

Abstract

Oxysterols are oxygenated derivatives of cholesterol that may be formed endogenously or absorbed from the diet. Significant amounts of oxysterols have frequently been identified in foods of animal origin, in particular highly processed foods. To date, oxysterols have been shown to possess diverse biological activities; however, recent attention has focused on their potential role in the development of atherosclerosis. Oxysterols have been reported to induce apoptosis in cells of the arterial wall, a primary process in the development of atheroma. The aim of the present study was to identify the role of the mitochondria in the apoptotic pathways induced by the oxysterols 7b-hydroxycholesterol (7b-OH) and cholesterol-5b,6b-epoxide (b-epoxide) in U937 cells. To this end, we investigated the effects of these oxysterols on mitochondrial membrane potential, caspase-8 activity, the mitochondrial permeability transition pore and cytochrome c release. 7b-OH-induced apoptosis was associated with a loss in mitochondrial membrane potential after 2 h, accompanied by cytochrome c release from the mitochondria into the cytosol after 16 h. Pre-treatment with a range of inhibitors of the mitochondrial permeability transition pore protected against 7b-OH-induced cell death. In contrast, b-epoxide induced a slight increase in caspase-8 activity but had no effect on mitochondrial membrane potential or cytochrome c release. The present results confirm that 7b-OH-induced apoptosis occurs via the mitochondrial pathway and highlights differences in the apoptotic pathways induced by 7b-OH and b-epoxide in U937 cells.

Induction of apoptosis by 7-piperazinethylchrysin in HCT-116 human colon cancer cells

“…Previous studies have shown that a number of anticancer drugs induce apoptosis through the activation of the caspase pathways and the mitochondrial membrane dysfunction. Accumulating evidence indicates that mitochondria play a pivotal role in the apoptotic process in mammalian cells (22)(23)(24). Disruption of mitochondrial ∆Ψm is considered to be an indicator of mitochondria damage and is generally defined as an early stage of apoptosis, preceding efflux of small molecules from the mitochondria (including cytochrome c, apoptosis-inducing factor) and followed by caspase-9/-3 cascade activation (25)(26)(27)(28).…”

Cellular toxicity of oxycholesterols

“…(1,(6)(7)(8)(9)(10)(11)(12) Thus, OS have been isolated from some fresh foods and many processed foods: dairy, egg, meat, cheese, fish products, fried foods and frying media. (1,5,7,10,12,13) For general reviews of OS origin, chemistry, biology, distribution and metabolism, the reader should refer to previous publications. (11,(13)(14)(15) In Table 1, we include a nomenclature of commonly encountered OS.…”

Anthocyanin-Rich Aronox Extract from <i>Aronia</i><i>melanocarpa</i> E Protects against 7β-Hydroxycholesterol-Induced Apoptosis of Endothelial Cells

“…Depolarization of the inner mitochondrial membrane is believed to be a key early event in cells undergoing apoptosis via the intrinsic pathway [39] . In this study, involvement of mitochondria in the 7 ␤ -hydroxycholesterol-induced apoptosis was investigated by measuring the changes in mitochondrial ⌬ and release of cytochrome c, the phenomena previously reported in oxysterol-treated cells [12,28] . The results obtained in this study confirmed the earlier observations, and additionally demonstrated that Aronox can prevent 7 ␤ -hydroxycholesterol-induced loss of mitochondrial ⌬ and the subsequent release of cytochrome c into the cytosol.…”

“…When HUVECs were exposed to 7 ␤ -hydroxycholesterol (20 g/ml), the mitochondrial ⌬ became depolarized, as shown by an increased green fluorescence ( fig. 4 a, It has been previously shown that 7 ␤ -hydroxycholesterol-induced apoptosis is associated with a disruption of mitochondrial membrane function, resulting in a release of cytochrome c from the mitochondria into the cytosol, where it may initiate the intrinsic pathway of apoptosis [28] . Therefore, we decided to investigate the effects of Aronox on the cytosolic level of cytochrome c in cells exposed to 7 ␤ -hydroxycholesterol.…”

“…Disruption of the mitochondrial membrane potential has been implicated in 7 ␤ -hydroxycholesterol-induced apoptosis [28] . To test whether the anti-apoptotic effect of Aronox is mediated by inhibition of mitochondrial disruption, we investigated the influence of Aronox on mitochondrial ⌬ in the presence of 7 ␤ -hydroxycholesterol.…”