Cellular toxicity of oxycholesterols (original) (raw)
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FEBS Letters, 2005
Cholesterol, a major neutral lipid component of biological membranes and the lung epithelial lining fluids, is susceptible to oxidation by reactive oxygen and nitrogen species including ozone. The oxidation by ozone in biological environments results in the formation of 3b-hydroxy-5-oxo-5,6-secocholestan-6-al (cholesterol secoaldehyde or CSeco, major product) along with some other minor products. Recently, CSeco has been implicated in the pathogenesis of atherosclerosis and AlzheimerÕs disease. In this communication, we report that CSeco induces cytotoxicity in H9c2 cardiomyoblasts with an IC 50 of 8.9 ± 1.29 lM (n = 6). The observed effect of CSeco at low micromolar concentrations retained several key features of apoptosis, such as changes in nuclear morphology, phosphatidylserine externalization, DNA fragmentation, and caspase 3/7 activity. Treatment of cardiomyocytes with 5 lM CSeco for 24 h, for instance, resulted in 30.8 ± 3.28% apoptotic and 1.8 ± 1.11% of necrotic cells as against DMSO controls that only showed 1.3 ± 0.33% of apoptosis and 1.6 ± 0.67% of necrosis. In general, the loss of cellular viability paralleled the increased occurrence of apoptotic cells in various CSeco treatments. This study, for the first time, demonstrates the induction of apoptotic cell death in cardiomyocytes by a cholesterol ozonation product, implying a role for ozone in myocardial injury.
Oxyphytosterol formation in humans: Identification of high vs. low oxidizers
Biochemical Pharmacology, 2013
Cholesterol oxidation products (oxycholesterols) can be derived from dietary intake and from in vivo oxidation by specific enzymes or by reactive oxygen species (ROS) [1]. Increased oxycholesterol concentrations are found in plasma of patients suffering from cardiovascular disease (CVD) [2] and in atherosclerotic plaques [3]. Further, a positive correlation has been observed between ROSinduced oxycholesterol concentrations in serum and established CVD risk factors, such as obesity and increased triglyceride concentrations [4]. In addition, recent studies have also suggested that oxycholesterols contribute to the development of degenerative diseases such as age-related macular degeneration [5]. Although these findings are suggestive, causal relations between elevated plasma oxycholesterol concentrations and pathological conditions have not been established so far. Plant sterols are structurally related to cholesterol and can be oxidized to oxyphytosterols [6]. While the biological role of oxycholesterols has been studied into large detail [1,7], studies evaluating the formation, kinetics and (patho)physiological effects of oxyphytosterols are scarce. Oxycholesterols and oxyphytosterols exert cytotoxic and apoptotic effects in vitro, as indicated by an
OXIDIZED PRODUCTS OF CHOLESTEROL: DIETARY AND METABOLIC ORIGIN AND PROATHEROSCLEROTIC EFFECTS
Cholesterol oxidation products, termed oxysterols, are increasingly considered of potential interest in the pathogenesis of atherosclerotic lesions. Of dietary or endogenous origin, oxysterols may occur in significant amounts in low density lipoprotein (LDL) particles, especially in hypercholesterolemic subjects. They likely contribute to the uptake of modified LDL by scavenger receptors, and some of them finally accumulate in the subintimal space of major arteries; here cholesterol oxides may favor the perpetuation of a chronic inflammatory state, through their ability to trigger irreversible damage of vascular cells with consequent activation of phagocytes. Furthermore, practically all oxysterols of major pathophysiologic interest have been shown to markedly up-regulate expression and synthesis of adhesion molecules, inflammatory cytokines and chemokines. Cholesterol oxidation thus appears to be an important biochemical pathway through which it exerts toxic, inflammatory and finally atherogenic effects.
The Journal of Nutritional Biochemistry, 2002
Cholesterol oxidation products, termed oxysterols, are increasingly considered of potential interest in the pathogenesis of atherosclerotic lesions. Of dietary or endogenous origin, oxysterols may occur in significant amounts in low density lipoprotein (LDL) particles, especially in hypercholesterolemic subjects. They likely contribute to the uptake of modified LDL by scavenger receptors and some of them finally accumulate in the subintimal space of major arteries; here cholesterol oxides may favor the perpetuation of a chronic inflammatory state, through their ability to trigger irreversible damage of vascular cells with consequent activation of phagocytes. Furthermore, practically all oxysterols of major pathophysiologic interest have been shown to markedly up-regulate expression and synthesis of adhesion molecules, inflammatory cytokines and chemokines. Cholesterol oxidation thus appears to be an important biochemical pathway through which it exerts toxic, inflammatory and finally atherogenic effects.
Bioscience, Biotechnology, and Biochemistry, 2008
Sterol oxidation products derived from cholesterol and phytosterol are formed during the processing and storage of foods. The objective of the present study was to assess the potential unfavorable effects of oxysterols in mice. C57BL/6J mice were fed an AIN-93G-based diet containing 0.2 g/kg of oxycholesterol or oxyphytosterol for 4 weeks. The most abundant oxysterol in the diet was 7-ketosterol, but -epoxycholesterol, -epoxycholesterol, or 7-hydroxyphytosterol, and 7-hydroxyphytosterol were more prominent than 7-ketosterol in the serum and liver respectively. Consumption of both oxysterols resulted in an increased in 4-hydroxycholesterol and total oxycholesterol in the liver, but the oxycholesterol-fed mice had a lower level of cerebral 24S-hydroxycholesterol and a higher level of the serum triacylglycerols than the control and oxyphytosterol groups. These results indicate that both oxysterols in the diet are accumulated in the body, but that the biological effect of oxycholesterol is different from that of oxyphytosterol.
Journal of Neurochemistry, 2009
Oligodendrocytes are glial cells that form myelin sheaths in the CNS. In several pathologies like multiple sclerosis (McQualter and Bernard 2007) and Alzheimer's disease (AD) (Roth et al. 2005), oligodendrocytes are involved in an inflammatory process associated with increased levels of eicosanoids, cytokines, and inflammatory enzymes such as secreted phospholipase A2 (sPLA2). The levels of oxysterols, cholesterol oxidation products, are also altered in these diseases. In particular, the concentration of 24(S)-hydroxycholesterol (OH), also known as cerebrosterol [for review
Journal of Biomedicine and Biotechnology, 2009
Smooth muscle cells (SMCs) undergo changes related to proliferation and apoptosis in the physiological remodeling of vessels and in diseases such as atherosclerosis and restenosis. Recent studies also have demonstrated the vascular cell proliferation and programmed cell death contribute to changes in vascular architecture in normal development and in disease. The present study was designed to investigate the apoptotic pathways induced by 25-hydroxycholesterol in SMCs cultures, using an in vivo/in vitro cell model in which SMCs were isolated and culture from chicken exposed to an atherogenic cholesterol-rich diet (SMC-Ch) and/or an antiatherogenic fish oil-rich diet (SMC-Ch-FO). Cells were exposed in vitro to 25-hydroxycholesterol to study levels of apoptosis and apoptotic proteins Bcl-2, Bcl-X L and Bax and the expression of bcl-2 and bcl-x L , genes. The quantitative real-time reverse transcriptase-polymerase chain reaction and the Immunoblotting western blot analysis showed that 25-hydroxycholesterol produces apoptosis in SMCs, mediated by a high increase in Bax protein and Bax gene expression. These changes were more marked in SMC-Ch than in SMC-Ch-FO, indicating that dietary cholesterol produces changes in SMCs that make them more susceptible to 25-hydroxycholesterol-mediated apoptosis. Our results suggest that the replacement of a cholesterol-rich diet with a fish oil-rich diet produces some reversal of cholesterol-induced changes in the apoptotic pathways induced by 25-hydroxycholesterol in SMCs cultures, making SMCs more resistant to apoptosis.
Biochemical and Biophysical Research Communications, 2003
Atherosclerosis involves inflammatory processes, as well as cytotoxic and oxidative reactions. In atherosclerotic plaques, these phenomena are revealed by the presence of dead cells, oxidized lipids, and oxidative DNA damage, but the molecules triggering these events are still unknown. As 7b-hydroxycholesterol and 7-ketocholesterol, which are present at elevated concentrations in atherosclerotic lesions, are strongly cytotoxic and pro-oxidative, their effects were determined on cell death, superoxide anion and nitric oxide production, lipid peroxidation, and oxidative DNA damage. 7-Ketocholesterol-and 7b-hydroxycholesterol-induced cell death leads to a loss of mitochondrial potential, to increased permeability to propidium iodide, and to morphological nuclear changes (swelling, fragmentation, and/or condensation of nuclei). These effects are preceded by the formation of cytoplasmic monodansylcadaverine-positive structures and are associated with a rapid enhancement of cells overproducing superoxide anions, a decrease in cells producing nitric oxide, lipid peroxidation (formation of malondialdehyde and 4-hydroxynonenal adducts, low ratio of [unsaturated fatty acids]/[saturated fatty acids]) as well as oxidative DNA damage (8-oxoguanine formation). Noteworthy, none of the cytotoxic features previously observed with 7b-hydroxycholesterol and 7-ketocholesterol were noted with cholesterol, 7bhydroxycholesteryl-3-oleate and 7-ketocholesteryl-3-oleate, with the exception of a slight increase in superoxide anion production with 7b-hydroxycholesteryl-3-oleate. This finding supports the theory that 7b-hydroxycholesterol and 7-ketocholesterol could induce cytotoxic and oxidative processes observed in atherosclerotic lesions and that esterification of these compounds may contribute to reducing atherosclerosis progression.
Cholesterol oxidation: Health hazard and the role of antioxidants in prevention
Biological Research, 2003
BIOLOGICAL IMPORTANCE OF CHOLESTEROL Sterol cholesterol (cholest-5-en-ß-ol) is an essential metabolite required for major biological functions, such as the cell membrane structure where the steroid f o r m s , t o g e t h e r w i t h p h o s p h o l i p i d molecules, the integral part of the lipid b i l a y e r (S p e c t o r & Y o r e k , 1 9 8 5). Cholesterol is inserted into membrane bilayers with its long axis perpendicular to the plane of the membrane, preventing the crystallization of fatty acyl chains by fitting b e t w e e n t h e m (Y e a g l e , 1 9 8 5) a n d modifying the activity of membranebounded enzymes (Valencia et al., 1999). Cholesterol also provides the structural scaffolding for the synthesis of steroids a n d s t e r o i d h o r m o n e s , a n d f o r t h e biosynthesis of bile and bile acid salts. Sterol plays also an important role in embryonic development (Roux et al., 2000).