1. The role of autophagy in survival response induced by 27-hydroxycholesterol in human promonocytic cells
- Author
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Paola Gamba, Huveyda Basaga, Simona Gargiulo, Beyza Vurusaner, Gabriella Testa, Gabriella Leonarduzzi, and Giuseppe Poli
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,PKCs, protein kinases C ,Clinical Biochemistry ,Apoptosis ,Monocyte-Macrophage Precursor Cells ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Survival signaling ,chemistry.chemical_compound ,PVDF, polyvinylidene difluoride ,ERK, extracellular signal-regulated kinase ,SMCs, smooth muscle cells ,MAPKs, mitogen-activated protein kinases ,lcsh:QH301-705.5 ,HO-1, heme oxygenase-1 ,lcsh:R5-920 ,DPI, diphenyleneiodonium chloride ,HNE, 4-hydroxy-trans-2-nonenal ,oxLDLs, oxidized low density lipoproteins ,RNA-Binding Proteins ,ROS ,Oxysterols ,3. Good health ,Cell biology ,Keap1, Kelch-like ECH-associated protein 1 ,Cholesterol ,27-Hydroxycholesterol ,lipids (amino acids, peptides, and proteins) ,Nrf2, nuclear factor erythroid 2 p45-related factor 2 ,medicine.symptom ,lcsh:Medicine (General) ,PI3K, phosphoinositide 3-kinase ,Research Paper ,Oxysterol ,27-hydroxycholesterol ,Cell Survival ,NF-E2-Related Factor 2 ,Inflammation ,ARE, antioxidant response element ,mTOR, mammalian target of rapamycin ,03 medical and health sciences ,ROS, reactive oxygen species ,FBS, fetal bovine serum ,medicine ,Autophagy ,Humans ,PAGE, SDS-polyacrylamide gel electrophoresis ,Protein kinase B ,JNK, c-Jun NH2-terminal kinase ,RT-PCR, reverse transcription–polymerase chain reaction ,PI3K/AKT/mTOR pathway ,FITC, fluorescein isothiocyanate fluorochrome ,Organic Chemistry ,Atherosclerosis ,Hydroxycholesterols ,AMPK, AMP-activated protein kinase ,Oxidative Stress ,030104 developmental biology ,lcsh:Biology (General) ,chemistry ,siRNA, small interfering RNA ,NAC, N-acetyl cysteine ,27-OH, 27-hydroxycholesterol ,7-K, 7-ketocholesterol ,MEK, mitogen-activated protein kinase ERK kinase ,Reactive Oxygen Species ,Oxidative stress - Abstract
Autophagy has been shown to be stimulated in advanced atherosclerotic plaques by metabolic stress, inflammation and oxidized lipids. The lack of published studies addressing the potential stimulation of pro-survival autophagy by oxysterols, a family of cholesterol oxidation products, has prompted our study. Thus, the goal of the current study is to elucidate the molecular mechanism of the autophagy induced by 27-hydroxycholesterol (27-OH), that is one of the most abundant oxysterols in advanced atherosclerotic lesions, and to assess whether the pro-oxidant effect of the oxysterol is involved in the given response. Here we showed that 27-OH, in a low micromolar range, activates a pro-survival autophagic response in terms of increased LC3 II/LC3 I ratio and Beclin 1, that depends on the up-regulation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways as a potential result of an intracellular reactive oxygen species increase provoked by the oxysterol in human promonocytic U937 cells. Moreover, 27-OH induced autophagy is dependent on the relation between nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-dependent antioxidant response and p62. The data obtained highlight the involvement of cholesterol oxidation products in the pathogenesis of oxidative stress related chronic diseases like atherosclerosis. Therefore, deeply understanding the complex mechanism and generating synthetic or natural molecules targeting this survival mechanism might be very promising tools in the prevention of such diseases., Graphical abstract A hypothetical scheme for 27-hydroxycholesterol (27-OH) involvement in autophagy modulated survival signaling.fx1, Highlights • Low concentrations of 27-OH activates autophagy in human promonocytic cells. • Pharmacological inhibition of ERK or Akt pathways prevents autophagy. • Nrf2/p62 pathway affects the autophagy response induced by 27-OH.
- Published
- 2018