Sildenafil Inhibits Advanced Glycation End Products-induced sFlt-1 Release Through Upregulation of Heme Oxygenase-1

Jeong, Jae Hyeok; Kim, Hwi Gon; Choi, Ook Hwan

doi:10.6118/jmm.2014.20.2.57

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…In this context, studies with human umbilical vein endothelial cells and trophoblasts highlight the importance of bilirubin in angiogenesis, particularly in the regulation of spiral artery remodeling (Ha et al, 2015). Moreover, in choriocarcinoma cells, it has been shown that the up-regulation of HMOX1 or exposure to bilirubin prevents advanced glycation end-product induced generation of sFTL-1, the soluble decoy receptor for VEGF, known to play a critical role in the pathogenesis of PE (Jeong et al, 2014). However, it is worth noting that placenta-derived soluble factors involved in maternal hypertension act by increasing endothelin-1 production from endothelial cells.…”

Section: Bilirubin and Vascular Dysfunctions In Pregnancymentioning

confidence: 99%

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

2020

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Among antioxidants in the human body, bilirubin has been recognized over the past 20 years to afford protection against different chronic conditions, including inflammation and cardiovascular disease. Moderate increases in plasma concentration and cellular bilirubin generation from metabolism of heme via heme oxygenase (HMOX) in virtually all tissues can modulate endothelial and vascular function and exert antioxidant and antiinflammatory roles. This review aims to provide an up-to-date and critical overview of the molecular mechanisms by which bilirubin derived from plasma or from HMOX1 activation in vascular cells affects endothelial function. Understanding the molecular actions of bilirubin may critically improve the management not only of key cardiovascular diseases, but also provide insights into a broad spectrum of pathologies driven by endothelial dysfunction. In this context, therapeutic interventions aimed at mildly increasing serum bilirubin as well as bilirubin generated endogenously by endothelial HMOX1 should be considered.

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Section: Bilirubin and Vascular Dysfunctions In Pregnancymentioning

confidence: 99%

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

2020

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“…They observed that AGEs-BSA increased sFlt-1 mRNA expression and protein release as well as increasing the production of ROS and NF- κ B in JEG-3. Sildenafil citrate suppressed sFlt-1 mRNA expression and protein release in cells treated with AGEs-Bovine Serum Albumin in a dose-dependent manner (concentration range 5–100 μ mol/mL) [ 56 ].…”

Section: Studies Performed In Humansmentioning

confidence: 99%

Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

Kniotek

Boguska

2017

Journal of Immunology Research

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Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system.

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“…For example, HO-1 expression in mouse placenta demonstrated also a dose- and time-dependent protection following exposure to LPS [ 66 ]. Interestingly, almost all of these protecting agents are also potent HO-1 inducers [ 67 , 68 , 69 , 70 , 71 ], suggesting that HO-1 also protects against the injurious effects of other TLR4-ligands besides heme.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice

Suttorp

Rheden

Dijk

et al. 2020

IJMS

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Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated that exposure of pregnant mice to heme during palatogenesis would initiate oxidative and inflammatory stress, leading to pathological pregnancy, increasing the incidence of palatal clefting and abortion. Both heme oxygenase isoforms (HO-1 and HO-2) break down heme, thereby generating anti-oxidative and -inflammatory products. HO may thus counteract these heme-induced injurious stresses. To test this hypothesis, we administered heme to pregnant CD1 outbred mice at Day E12 by intraperitoneal injection in increasing doses: 30, 75 or 150 μmol/kg body weight (30H, 75H or 150H) in the presence or absence of HO-activity inhibitor SnMP from Day E11. Exposure to heme resulted in a dose-dependent increase in abortion. At 75H half of the fetuses where resorbed, while at 150H all fetuses were aborted. HO-activity protected against heme-induced abortion since inhibition of HO-activity aggravated heme-induced detrimental effects. The fetuses surviving heme administration demonstrated normal palatal fusion. Immunostainings at Day E16 demonstrated higher numbers of ICAM-1 positive blood vessels, macrophages and HO-1 positive cells in placenta after administration of 75H or SnMP + 30H. Summarizing, heme acts as an endogenous “alarmin” during pregnancy in a dose-dependent fashion, while HO-activity protects against heme-induced placental vascular inflammation and abortion.

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Sildenafil Inhibits Advanced Glycation End Products-induced sFlt-1 Release Through Upregulation of Heme Oxygenase-1

Cited by 5 publications

References 48 publications

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice

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