Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols

Li, Wei; Ghosh, Moumita; Eftekhari, Sina; Yuan, Xi

doi:10.1016/j.bbrc.2011.05.071

Cited by 36 publications

(33 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…That 7kCHOL and other oxysterols exert toxic effects on a variety of cells in culture is well-documented (Li et al, 2011; Pedruzzi et al, 2004; Rodriguez et al, 2004). However, our findings represent the first report on the effects of such oxysterols using pure cultures of photoreceptor cell-derived cell lines.…”

Section: Discussionmentioning

confidence: 99%

Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: Dependence on sterol structure, cell type, and density

Pfeffer

Porter

et al. 2016

Experimental Eye Research

View full text Add to dashboard Cite

Tissue accumulation of 7-dehydrocholesterol (7DHC) is a hallmark of Smith-Lemli-Opitz Syndrome (SLOS), a human inborn error of the cholesterol (CHOL) synthesis pathway. Retinal 7DHC-derived oxysterol formation occurs in the AY9944-induced rat model of SLOS, which exhibits a retinal degeneration characterized by selective loss of photoreceptors and associated functional deficits, Müller cell hypertrophy, and engorgement of the retinal pigment epithelium (RPE) with phagocytic inclusions. We evaluated the relative effects of four 7DHC-derived oxysterols on three retina-derived cell types in culture, with respect to changes in cellular morphology and viability. 661W (photoreceptor-derived) cells, rMC-1 (Müller glia-derived) cells, and normal diploid monkey RPE (mRPE) cells were incubated for 24 h with dose ranges of either 7-ketocholesterol (7kCHOL), 5,9-endoperoxy-cholest-7-en-3β,6α-diol (EPCD), 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), or 4β-hydroxy-7-dehydrocholesterol (4HDHC); CHOL served as a negative control (same dose range), along with appropriate vehicle controls, while staurosporine (Stsp) was used as a positive cytotoxic control. For 661W cells, the rank order of oxysterol potency was: EPCD > 7kCHOL >> DHCEO > 4HDHC ≈ CHOL. EC50 values were higher for confluent vs. subconfluent cultures. 661W cells exhibited much higher sensitivity to EPCD and 7kCHOL than either rMC-1 or mRPE cells, with the latter being the most robust when challenged, either at confluence or in sub-confluent cultures. When tested on rMC-1 and mRPE cells, EPCD was again an order of magnitude more potent than 7kCHOL in compromising cellular viability. Hence, 7DHC-derived oxysterols elicit differential cytotoxicity that is dose-, cell type-, and cell density-dependent. These results are consistent with the observed progressive, photoreceptor-specific retinal degeneration in the rat SLOS model, and support the hypothesis that 7DHC-derived oxysterols are causally linked to that retinal degeneration as well as to SLOS.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: Dependence on sterol structure, cell type, and density

Pfeffer

Porter

et al. 2016

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…The induction of ROS production of endothelial cells by 7-KC can be important in the pathogenesis of vascular diseases by decreasing cell viability and induction various signaling pathways. 7-KC induces apoptosis of mouse aortic endothelial cells and human umbilical vein endothelial cells via increase of ROS production, mitochondrial permeabilization and Ca2+ mobilization [22, 23]. …”

Section: Discussionmentioning

confidence: 99%

7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells

et al. 2016

View full text Add to dashboard Cite

Cardiovascular diseases (atherosclerosis, stroke, myocardiac infarction etc.) are the major systemic diseases of elder peoples in the world. This is possibly due to increased levels of oxidized low-density lipoproteins (oxLDLs) such as 7-ketocholesterol (7-KC) and lysophosphatidylcholine (LPC) that damage vascular endothelial cells, induce inflammatory responses, to elevate the risk of cardiovascular diseases, Alzheimer's disease, and age-related macular degeneration. However the toxic effects of 7-KC on endothelial cells are not known. In this study, 7-KC showed cytotoxicity to endothelial cells at concentrations higher than 10 μg/ml. 7-KC stimulated ATM/Chk2, ATR-Chk1 and p53 signaling pathways in endothelial cells. 7-KC also induced G0/G1 cell cycle arrest and apoptosis with an inhibition of Cyclin dependent kinase 1 (Cdk1) and cyclin B1 expression. Secretion and expression of IL-8 in endothelial cells were stimulated by 7-KC. 7-KC further induced intracellular ROS production as shown by increase in DCF fluorescence and Akt phosphorylation. LY294002 attenuated the 7-KC-induced apoptosis and IL-8 mRNA expression of endothelial cells. These results indicate that oxLDLs such as 7-KC may contribute to the pathogenesis of atherosclerosis, thrombosis and cardiovascular diseases by induction of endothelial damage, apoptosis and inflammatory responses. These events are associated with ROS production, activation of ATM/Chk2, ATR/Chk1, p53 and PI3K/Akt signaling pathways.

show abstract

“…Targeting different cellular models, 7-ketocholesterol has been extensively reported to cause death by apoptosis both through the extrinsic and intrinsic pathways, featuring reduction of the A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 mitochondrial membrane potential, release of cytochrome C and production of reactive oxygen species [19,[24][25][26][27]. Recently, 7KC has been suggested to induce a complex form of cell death, oxiapoptophagy, characterized by reduction of cell proliferation, increased membrane permeability, nucleus condensation, decreased production of nitric oxide and oxidative damage to DNA [28,29].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Rosa-Fernandes

Stern

Cavaglieri

et al. 2017

Journal of Proteomics

View full text Add to dashboard Cite

Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols

Cited by 36 publications

References 27 publications

Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: Dependence on sterol structure, cell type, and density

Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: Dependence on sterol structure, cell type, and density

7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells

7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism

Contact Info

Product

Resources

About