scholarly journals Peroxisome Proliferator-Activated Receptor-γ Antagonizes LOX-1-Mediated Endothelial Injury by Transcriptional Activation of miR-590-5p

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Lei Xu ◽  
Gang Zhao ◽  
Hong Zhu ◽  
Shijun Wang ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Umbilical Vein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the major receptors expressed on the endothelium of arterial wall with a key role in endothelial dysfunction and the development of atherosclerosis. Recent evidence suggested that LOX-1 is upregulated under the condition of insulin resistance and could be suppressed by the antidiabetic drugs. We previously also confirmed that Thiazolidinedione (TZD) has the inhibitory effect on LOX-1 in ox-LDL-induced endothelial cells. However, the underlying mechanism is unclear. Here we showed that Rosiglitazone treatment significantly attenuated the expressions of LOX-1, ICAM-1, VCAM-1, p47phox, and the atherosclerotic lesions in ApoE-/- mice with high-fat diet. In vitro, we revealed that Rosiglitazone inhibited LOX-1 by regulating miR-590-5p. Ox-LDL-mediated ICAM-1, VCAM-1, and p47phox were significantly reduced by Rosiglitazone, but all reversed after pretreating the cells with antagomiR-590-5p. Induction with Rosiglitazone activated PPAR-γ and promoted its nuclear translocation in cultured human umbilical vein endothelial cells (HUVECs). The nuclear PPAR-γ upregulated the miR-590-5p level through binding to its transcriptional promoter region. Retaining PPAR-γ in cytoplasm by transfecting with PPAR-γ⊿NLS plasmid in HUVECs failed to activate miR-590-5p. Mutation of the promoter region of PPAR-γ also reduced the miR-590-5p promoter luciferase activity. Collectively, these data indicated that PPAR-γ may have the therapeutic potential in atherosclerosis via the transcriptional regulation of miR-590-5p in endothelial cells.

scholarly journals PPAR-αAgonist Fenofibrate Upregulates Tetrahydrobiopterin Level through Increasing the Expression of Guanosine 5′-Triphosphate Cyclohydrolase-I in Human Umbilical Vein Endothelial Cells

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Jinbo Liu ◽  
Changlin Lu ◽  
Fuwang Li ◽  
Haining Wang ◽  
Liyun He ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. Guanosine 5′-triphosphate cyclohydrolase-I (GTPCH-I) is a key limiting enzyme for BH4 synthesis. In the present in vitro study, we investigated whether peroxisome proliferator-activated receptorα(PPAR-α) agonist fenofibrate could recouple eNOS by reversing low-expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms. After human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) for 24 hours, the levels of cellular eNOS, BH4 and cell supernatant NO were significantly reduced compared to control group. And the fluorescence intensity of intracellular ROS was significantly increased. But pretreated with fenofibrate (10 umol/L) for 2 hours before cells were induced by LPS, the levels of eNOS, NO, and BH4 were significantly raised compared to LPS treatment alone. ROS production was markedly reduced in fenofibrate group than LPS group. In addition, our results showed that the level of intracellular GTPCH-I detected by western blot was increased in a concentration-dependent manner after being treated with fenofibrate. These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH-I.

Oxidized low-density lipoprotein and 15-deoxy-Δ12,14-PGJ2 increase mitochondrial complex I activity in endothelial cells

2003 ◽  
Vol 285 (6) ◽  
pp. H2298-H2308 ◽  
Author(s):  
Erin K. Ceaser ◽  
Anup Ramachandran ◽  
Anna-Liisa Levonen ◽  
Victor M. Darley-Usmar
Keyword(s):  
Endothelial Cells ◽  
Complex I ◽  
Citrate Synthase ◽  
Umbilical Vein ◽  
Oxidized Ldl ◽  
Antioxidant Defenses ◽  
Oxidized Lipids ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Complex I Activity

Oxidized lipids are capable of initiating diverse cellular responses through both receptor-mediated mechanisms and direct posttranslational modification of proteins. Typically, exposure of cells to low concentrations of oxidized lipids induces cytoprotective pathways, whereas high concentrations result in apoptosis. Interestingly, mitochondria can contribute to processes that result in either cytoprotection or cell death. The role of antioxidant defenses such as glutathione in adaptation to stress has been established, but the potential interaction with mitochondrial function is unknown and is examined in this article. Human umbilical vein endothelial cells (HUVEC) were exposed to oxidized LDL (oxLDL) or the electrophilic cyclopentenone 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). We demonstrate that complex I activity, but not citrate synthase or cytochrome- c oxidase, is significantly induced by oxLDL and 15d-PGJ2. The mechanism is not clear at present but is independent of the induction of GSH, peroxisome proliferator-activated receptor (PPAR)-γ, and PPAR-α. This response is dependent on the induction of oxidative stress in the cells because it can be prevented by nitric oxide, probucol, and the SOD mimetic manganese(III) tetrakis(4-benzoic acid) porphyrin chloride. This increased complex I activity appears to contribute to protection against apoptosis induced by 4-hydroxynonenal.

scholarly journals Liraglutide suppresses obesity and promotes browning of white fat via miR-27b in vivo and in vitro

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110550
Author(s):  
Xing Wang ◽  
Shuchun Chen ◽  
Dan Lv ◽  
Zelin Li ◽  
Luping Ren ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
White Adipocytes ◽  
White Fat

Objective To investigate the effect of liraglutide on the browning of white fat and the suppression of obesity via regulating microRNA (miR)-27b in vivo and in vitro. Methods Sprague-Dawley rats were fed a high-fat (HF) diet and 3T3-L1 pre-adipocytes were differentiated into mature white adipocytes. Rats and mature adipocytes were then treated with different doses of liraglutide. The mRNA and protein levels of browning-associated proteins, including uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), CCAAT enhancer binding protein β (CEBPβ), cell death-inducing DFFA-like effector A (CIDEA) and peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α), were detected using quantitative real-time polymerase chain reaction and Western blotting. Results Liraglutide decreased body weight and reduced the levels of blood glucose, triglyceride and low-density lipoprotein cholesterol in HF diet-fed rats. Liraglutide increased the levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α in vivo and vitro. The levels of miR-27b were upregulated in HF diet-fed rats, whereas liraglutide reduced the levels of miR-27b. In vitro, overexpression of miR-27b decreased the mRNA and protein levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α. Transfection with the miR-27b mimics attenuated the effect of liraglutide on the browning of white adipocytes. Conclusion Liraglutide induced browning of white adipose through regulation of miR-27b.

scholarly journals Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

2019 ◽  
Vol 20 (22) ◽  
pp. 5589
Author(s):  
Jaeim Lee ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jin Sun Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Therapeutic Potential ◽  
Tissue Expression ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Adipose Derived Stem Cells ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

scholarly journals The Role of PPARγin the Transcriptional Control by Agonists and Antagonists

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Tamotsu Tsukahara
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Control ◽  
Thyroid Hormone Receptor ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclic Phosphatidic Acid

In recent years, peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to be a target for the treatment of type II diabetes. Furthermore, it has received attention for its therapeutic potential in many other human diseases, including atherosclerosis, obesity, and cancers. Recent studies have provided evidence that the endogenously produced PPARγ antagonist, 2,3-cyclic phosphatidic acid (cPA), which is similar in structure to lysophosphatidic acid (LPA), inhibits cancer cell invasion and metastasisin vitroandin vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. We then analyzed the molecular mechanism of cPA's action on PPARγ. In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

scholarly journals Peroxisome Proliferator-Activated ReceptorγRegulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Yazi Huang ◽  
Beilei Zhao ◽  
Yahan Liu ◽  
Nanping Wang
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Mrna Level ◽  
Site Directed Mutagenesis ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphohydrolase

Lipid phosphate phosphohydrolase 1 (LPP1), a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptorγ(PPARγ) in the transcriptional control ofLPP1gene expression. In human umbilical vein endothelial cells (HUVECs), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) demonstrated that activation of PPARγincreased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPARγbinds to the putative PPAR-responsive elements (PPREs) within the 5′-flanking region of the humanLPP1gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPARγand rosiglitazone, a specific ligand for PPARγ, could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPARγtranscriptionally activated the expression ofLPP1gene in ECs, suggesting a potential role of PPARγin the metabolism of phospholipids.

PPARs and angiogenesis

2011 ◽  
Vol 39 (6) ◽  
pp. 1601-1605 ◽  
Author(s):  
David Bishop-Bailey
Keyword(s):  
Endothelial Cells ◽  
Critical Role ◽  
Molecular Target ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Angiogenic Switch ◽  
Receptor Family

The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPARα, PPARβ/δ and PPARγ. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPARγ, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPARγ was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPARα, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPARα or PPARγ, activation of PPARβ/δ induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPARβ/δ is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail.

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