2004
DOI: 10.1128/mcb.24.24.10703-10717.2004
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NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

Abstract: The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase … Show more

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Cited by 383 publications
(345 citation statements)
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“…Further, because free cholesterol activates apoptosis through the endoplasmic reticulum pathway (57), the intracellular accumulation of free cholesterol triggered by 7KC can stimulate some components of the endoplasmic reticulum, which in turn can induce 7KC-induced apoptosis. This hypothesis is supported by the expression of the cell death effector CHOP and GRP78/ bip chaperone, which are hallmarks of the unfolded protein response (58), and by the synthesis of similar cytoplasmic structures occurring under treatment with 7KC and free cholesterol (22,23,57,59). At the cytoplasmic level, the presence of myelin figures observed during 7KC-induced apoptosis (22,23) evokes phospholipid whorls formed during cell death of murine macrophages induced by free cholesterol (54).…”
Section: Discussionmentioning
confidence: 91%
“…Further, because free cholesterol activates apoptosis through the endoplasmic reticulum pathway (57), the intracellular accumulation of free cholesterol triggered by 7KC can stimulate some components of the endoplasmic reticulum, which in turn can induce 7KC-induced apoptosis. This hypothesis is supported by the expression of the cell death effector CHOP and GRP78/ bip chaperone, which are hallmarks of the unfolded protein response (58), and by the synthesis of similar cytoplasmic structures occurring under treatment with 7KC and free cholesterol (22,23,57,59). At the cytoplasmic level, the presence of myelin figures observed during 7KC-induced apoptosis (22,23) evokes phospholipid whorls formed during cell death of murine macrophages induced by free cholesterol (54).…”
Section: Discussionmentioning
confidence: 91%
“…Pedruzzi et al [16] reported that Nox4 activity located in the endoplasmic reticulum was concomitant to Ca 2+ oscillation after exposure to 7-ketocholesterol. However in a previous study, we showed that ionomycin (calcium ionophore) had no effect on the Nox4 activity in chondrocytes C-20/A4 cells over-expressing Nox4A [18].…”
Section: Stimulation Of Nox4 Activity By Two Quinone Derivativesmentioning
confidence: 99%
“…Primary discovered in kidney tissue [13], Nox4 appears to be ubiquitously distributed. Its dysfunction has been linked to several pathologies including hypertension [14], diabetes [15], atherosclerosis [16], cancer [17], osteoarthritis [18] and inflammation [19], and Nox4 represent a potential therapeutic target [20]. Despite its wide distribution, its activation mechanisms at the molecular level are unclear.…”
Section: Introductionmentioning
confidence: 99%
See 1 more Smart Citation
“…Oxidative stress is increasingly implicated in the development of atherosclerosis (5) and increased oxidative damage, and elevated levels of DNA strand breaks occur in human atherosclerotic plaques (6). Oxidative stress reduces IGF1R expression and induces VSMC apoptosis in culture (7)(8)(9)(10). Reduced IGF1R expression is also seen within plaques, suggesting that IGF1R-dependent survival regulates apoptosis in vivo (11,12).…”
mentioning
confidence: 99%