International Journal of Cardiology

2017

DOI: 10.1016/j.ijcard.2017.02.102

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PEDF improves atherosclerotic plaque stability by inhibiting macrophage inflammation response

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Pedf and Atherosclerosis1

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Oxidative Stress Inflammatory and Nutritive Factors Promote1

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Cited by 36 publications

(20 citation statements)

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“…In the endothelial cells, PEDF has been shown to inhibit the cellular permeability via p38MAPK de-activation (30). While, PEDF also protected against retinal neovascularization by suppression of p38MAPK activation and dampening iNOS induction in the macrophage (31,32). Likewise, our data showed that PEDF, by targeting NOXO1, protected mesangial cells from fibrogenesis and nitroxidative/nitrosative stress, at least partly via abrogation of p38MAPK mediated iNOS induction.…”

Section: Discussionsupporting

confidence: 61%

Pigment epithelium-derived factor protects human glomerular mesangial cells from diabetes via NOXO1-iNOS suppression

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2017

Molecular Medicine Reports

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The authors previously reported that pigment epithelium‑derived factor (PEDF) protects the diabetic kidney from fibrosis via its anti‑oxidative effects. However, the underlying molecular mechanism has never been revealed. The present study aimed to investigate how PEDF protects mesangial cells from diabetes induced damage. Human mesangial cells were exposed to a diabetic environment [30 mmol/l glucose and 200 mg advanced glycation end products (AGEs)] in the absence or presence of PEDF (200 mg/l). The superoxide and peroxynitrite productions were measured by fluorescent assay. The nicotinamide adenine dinucleotide phosphate (NAPDH) oxidases (NOXs; isoforms NOX1, NOX2, and NOX4), NADPH oxidase organizer 1 (NOXO1), DHFR, endothelial nitric oxide synthase (iNOS) and phospho‑p38MAPK (p‑p38) protein levels were also examined to explore the possible mechanism of the PEDF anti‑oxidative properties. The fibrogenesis of mesangial cells in diabetes was associated with increased superoxide generation and peroxynitrite production via iNOS induction and uncoupling. However, elevated transforming growth factor‑β level, reactive oxygen species (ROS) overproduction, iNOS induction and uncoupling were all reversed by NOXO1 suppression following PEDF treatment or NOXO1 silencing. Furthermore, the p38MAPK inhibition only attenuated the ROS/peroxynitrite production partially via abolishment of iNOS induction, however had no effect on iNOS uncoupling and its regulating enzyme: DHFR suppression. PEDF prevented oxidative stress and protected mesangial cells from fibrogenesis in a diabetic environment via dual effects mediated by NOXO1 inhibitory prevention of iNOS induction through p38MAPK inactivation and effects on iNOS coupling through DHFR restoration.

“…In the endothelial cells, PEDF has been shown to inhibit the cellular permeability via p38MAPK de-activation (30). While, PEDF also protected against retinal neovascularization by suppression of p38MAPK activation and dampening iNOS induction in the macrophage (31,32). Likewise, our data showed that PEDF, by targeting NOXO1, protected mesangial cells from fibrogenesis and nitroxidative/nitrosative stress, at least partly via abrogation of p38MAPK mediated iNOS induction.…”

Section: Discussionsupporting

confidence: 61%

Pigment epithelium-derived factor protects human glomerular mesangial cells from diabetes via NOXO1-iNOS suppression

¹

,

²

,

³

2017

Molecular Medicine Reports

View full text Add to dashboard Cite

The authors previously reported that pigment epithelium‑derived factor (PEDF) protects the diabetic kidney from fibrosis via its anti‑oxidative effects. However, the underlying molecular mechanism has never been revealed. The present study aimed to investigate how PEDF protects mesangial cells from diabetes induced damage. Human mesangial cells were exposed to a diabetic environment [30 mmol/l glucose and 200 mg advanced glycation end products (AGEs)] in the absence or presence of PEDF (200 mg/l). The superoxide and peroxynitrite productions were measured by fluorescent assay. The nicotinamide adenine dinucleotide phosphate (NAPDH) oxidases (NOXs; isoforms NOX1, NOX2, and NOX4), NADPH oxidase organizer 1 (NOXO1), DHFR, endothelial nitric oxide synthase (iNOS) and phospho‑p38MAPK (p‑p38) protein levels were also examined to explore the possible mechanism of the PEDF anti‑oxidative properties. The fibrogenesis of mesangial cells in diabetes was associated with increased superoxide generation and peroxynitrite production via iNOS induction and uncoupling. However, elevated transforming growth factor‑β level, reactive oxygen species (ROS) overproduction, iNOS induction and uncoupling were all reversed by NOXO1 suppression following PEDF treatment or NOXO1 silencing. Furthermore, the p38MAPK inhibition only attenuated the ROS/peroxynitrite production partially via abolishment of iNOS induction, however had no effect on iNOS uncoupling and its regulating enzyme: DHFR suppression. PEDF prevented oxidative stress and protected mesangial cells from fibrogenesis in a diabetic environment via dual effects mediated by NOXO1 inhibitory prevention of iNOS induction through p38MAPK inactivation and effects on iNOS coupling through DHFR restoration.

“…In addition to the potent and selective anti-angiogenic function, PEDF has neuroprotective, antioxidant, anti-inflammation, and antithrombotic properties, and has been associated with therapy of atherosclerotic diseases, choroidal neovascularization, cancer, etc. (Takenaka et al, 2008 ; Rychli et al, 2009 ; Yamagishi and Matsui, 2010 , 2014 ; Wen et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside-Rb1-Mediated Anti-angiogenesis via Regulating PEDF and miR-33a through the Activation of PPAR-γ Pathway

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et al. 2017

Front. Pharmacol.

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Angiogenesis is the formation of new blood vessels from the existing vasculature, which is involved in multiple biological processes, including atherosclerosis, ischemic heart disease, and cancer. Ginsenoside-Rb1 (Rb1), the most abundant ginsenoside isolated form Panax ginseng, has been identified as a promising anti-angiogenic agent via the up-regulation of PEDF. However, the underlying molecular mechanisms still unknown. In the present study, human umbilical vein endothelial cells (HUVECs) were selected to perform in vitro assays. Rb1 (0–20 nM) treatment induced pigment epithelial-derived factor (PEDF) protein expression in concentration and time-dependent manners. Interestingly, it was also demonstrated that the exposure of Rb1 (10 nM) could increase PEDF protein expression without any alteration on mRNA level, suggesting the involvement of posttranscriptional regulation. Furthermore, bioinformatics predictions indicated the regulation of miR-33a on PEDF mRNA 3′-UTR, which was further confirmed by luciferase reporter gene assay and real-time PCR. Over-expression of pre-miR-33a was found to regress partly Rb1-mediated PEDF increment and anti-angiogenic effect in HUVECs. Additionally, Rb1-reduced miR-33a and increased PEDF expression was prevented by pre-incubation with peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist (GW9662) or transfection with PPAR-γ siRNA in HUVECs. Taken together, our findings demonstrated that Rb1 exerted anti-angiogenic effects through PPAR-γ signaling pathway via modulating miR-33a and PEDF expressions. Thus, Rb1 may have the potential of being developed as an anti-angiogenic agent, however, further appropriate studies are warranted to evaluate the effect in vivo.

“…The unstable plaque with chronic inflammation is a precursor for adverse cardiac outcomes. Wen H and colleagues have revealed that PEDF improves the stability of atherosclerotic plaques by ameliorating the macrophage inflammation response, which is closely associated with peroxisome proliferator-activated receptor γ (PPAR-γ) and downstream mitogen-activated protein kinase (MAPK) [ 116 ]. There is evidence suggesting that PEDF can inhibit occlusive thrombus formation by blocking platelet activation and aggregation [ 16 ], and it may prevent atherothrombosis in patients with diabetes mellitus by inhibiting the CD40-CD40L axis [ 117 , 118 ].…”

Section: Pedf and Atherosclerosismentioning

confidence: 99%

The effects of pigment epithelium-derived factor on atherosclerosis: putative mechanisms of the process

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et al. 2018

Lipids Health Dis

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Cardiovascular disease (CVD) is a leading cause of death worldwide. Atherosclerosis is believed to be the major cause of CVD, characterized by atherosclerotic lesion formation and plaque disruption. Although remarkable advances in understanding the mechanisms of atherosclerosis have been made, the application of these theories is still limited in the prevention and treatment of atherosclerosis. Therefore, novel and effective strategies to treat high-risk patients with atherosclerosis require further development. Pigment epithelium-derived factor (PEDF), a glycoprotein with anti-inflammatory, anti-oxidant, anti-angiogenic, anti-thrombotic and anti-tumorigenic properties, is of considerable interest in the prevention of atherosclerosis. Accumulating research has suggested that PEDF exerts beneficial effects on atherosclerotic lesions and CVD patients. Our group, along with colleagues, has demonstrated that PEDF may be associated with acute coronary syndrome (ACS), and that the polymorphisms of rs8075977 of PEDF are correlated with coronary artery disease (CAD). Moreover, we have explored the anti-atherosclerosis mechanisms of PEDF, showing that oxidized-low density lipoprotein (ox-LDL) reduced PEDF concentrations through the upregulation of reactive oxygen species (ROS), and that D-4F can protect endothelial cells against ox-LDL-induced injury by preventing the downregulation of PEDF. Additionally, PEDF might alleviate endothelial injury by inhibiting the Wnt/β-catenin pathway. These data suggest that PEDF may be a novel therapeutic target for the treatment of atherosclerosis. In this review, we will summarize the role of PEDF in the development of atherosclerosis, focusing on endothelial dysfunction, inflammation, oxidative stress, angiogenesis and cell proliferation. We will also discuss its promising therapeutic implications for atherosclerosis.

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