scholarly journals Melatonin Attenuates ox-LDL-Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Peng Li ◽  
Changlian Xie ◽  
Jiankai Zhong ◽  
Zhongzhou Guo ◽  
Kai Guo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mitochondrial Ros ◽  
Er Homeostasis

Endothelial dysfunction, which is characterized by damage to the endoplasmic reticulum (ER) and mitochondria, is involved in a variety of cardiovascular disorders. Here, we explored whether mitochondrial damage and ER stress are associated with endothelial dysfunction. We also examined whether and how melatonin protects against oxidized low-density lipoprotein- (ox-LDL-) induced damage in endothelial cells. We found that CHOP, GRP78, and PERK expressions, which are indicative of ER stress, increased significantly in response to ox-LDL treatment. ox-LDL also induced mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and downregulation of mitochondrial protective factors. In addition, ox-LDL inhibited antioxidative processes, as evidenced by decreased antioxidative enzyme activity and reduced Nrf2/HO-1 expression. Melatonin clearly reduced ER stress and promoted mitochondrial function and antioxidative processes in the presence of ox-LDL. Molecular investigation revealed that ox-LDL activated the JNK/Mff signaling pathway, and melatonin blocked this effect. These results demonstrate that ox-LDL induces ER stress and mitochondrial dysfunction and activates the JNK/Mff signaling pathway, thereby contributing to endothelial dysfunction. Moreover, melatonin inhibited JNK/Mff signaling and sustained ER homeostasis and mitochondrial function, thereby protecting endothelial cells against ox-LDL-induced damage.

scholarly journals HIV-1 Tat Regulates Occludin and AβTransfer Receptor Expression in Brain Endothelial Cells via Rho/ROCK Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yanlan Chen ◽  
Wen Huang ◽  
Wenlin Jiang ◽  
Xianghong Wu ◽  
Biao Ye ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Immunofluorescent Staining ◽  
Mrna Levels ◽  
Protein Levels ◽  
Density Lipoprotein Receptor ◽  
Hiv 1

HIV-1 transactivator protein (Tat) has been shown to play an important role in HIV-associated neurocognitive disorders. The aim of the present study was to evaluate the relationship between occludin and amyloid-beta (Aβ) transfer receptors in human cerebral microvascular endothelial cells (hCMEC/D3) in the context of HIV-1-related pathology. The protein expressions of occludin, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in hCMEC/D3 cells were examined using western blotting and immunofluorescent staining. The mRNA levels of occludin, RAGE, and LRP1 were measured using quantitative real-time polymerase chain reaction. HIV-1 Tat at 1 µg/mL and the Rho inhibitor hydroxyfasudil (HF) at 30 µmol/L, with 24 h exposure, had no significant effect on hCMEC/D3 cell viability. Treatment with HIV-1 Tat protein decreased mRNA and protein levels of occludin and LRP1 and upregulated the expression of RAGE; however, these effects were attenuated by HF. These data suggest that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-mediated changes in occludin, RAGE, and LRP1 in hCMEC/D3 cells. HF may have a beneficial influence by protecting the integrity of the blood-brain barrier and the expression of Aβtransfer receptors.

EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling

2010 ◽  
Vol 108 (6) ◽  
pp. 1745-1756 ◽  
Author(s):  
Hsiu-Chung Ou ◽  
Tuzz-Ying Song ◽  
Yueh-Chiao Yeh ◽  
Chih-Yang Huang ◽  
Shun-Fa Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ros Generation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Amino Terminal

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can downregulate parameters of endothelial dysfunction by modulating LOX-1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 μg/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well-known inhibitor of flavoproteins, suggesting the involvement of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47phox and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino-terminal region of Akt, with maximal induction at about 30 min, and NF-κB phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cytoprotective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-κB via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction.

scholarly journals Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis

2020 ◽  
Vol 126 (3) ◽  
pp. 298-314 ◽  
Author(s):  
Daniel J. Tyrrell ◽  
Muriel G. Blin ◽  
Jianrui Song ◽  
Sherri C. Wood ◽  
Min Zhang ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Tissue ◽  
Wild Type ◽  
Il Interleukin ◽  
Age Related ◽  
Density Lipoprotein Receptor ◽  
Young Mice

Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

β-Sitosterol regulated microRNAs in endothelial cells against an oxidized low-density lipoprotein

2020 ◽  
Vol 11 (2) ◽  
pp. 1881-1890 ◽  
Author(s):  
Yue-Hua Jiang ◽  
Xiao Li ◽  
Weipin Niu ◽  
DongLi Wang ◽  
Bo Wu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Mitochondrial Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Protective Effects ◽  
Oxidized Low Density Lipoprotein ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells

β-sitosterol is shown to demonstrate endothelial protective effects, which inhibited apoptosis, increased cell migration, and improved mitochondrial function of human aortic endothelial cells.

scholarly journals Curcumin Alleviates Palmitic Acid-Induced LOX-1 Upregulation by Suppressing Endoplasmic Reticulum Stress in HUVECs

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Ruixi Luo ◽  
Lifeng Zhao ◽  
Shuaishuai Li ◽  
Peng Chen ◽  
La Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Umbilical Vein ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Low Density

Excessive free fatty acid- (FFA-) induced endothelial lipotoxicity is involved in the pathogenesis of atherosclerosis. Endoplasmic reticulum (ER) stress is mechanistically related to endothelial lipotoxicity. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major oxidatively modified low-density lipoprotein (OxLDL) receptor in endothelial cells and is highly abundant in atherosclerotic lesions. Curcumin reduces the LOX-1 expression; however, the mechanism underlying this effect remains unknown. In the current study, we explored whether curcumin ameliorates palmitic acid- (PA-) induced endothelial lipotoxicity and LOX-1 upregulation by reducing ER stress in human umbilical vein endothelial cells (HUVECs). We built endothelial lipotoxicity in vitro and found that LOX-1 was upregulated after PA stimulation, during which ER stress played an important role. Next, we observed that curcumin substantially alleviated PA-induced lipotoxicity by restoring cell viability, increasing angiogenesis, and decreasing lipid deposition. Furthermore, LOX-1 upregulation in HUVECs was blocked by curcumin, possibly via ER stress suppression. Overall, our findings demonstrated that curcumin alleviates endothelial lipotoxicity and LOX-1 upregulation, and ER stress inhibition may play a critical role in this effect.

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