Disease relevance of SERPINF1

• PEDF, or a derivative, could potentially abate or restore vision loss from diabetic macular edema [1].
• Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability [1].
• The decrease in PEDF may disrupt the balance and be permissive for the formation of choroidal neovascularization (CNV) in AMD [2].
• Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study [3].
• The treatment of SCC cells with hypoxia increased the expression of PEDF as well as VEGF [4].

High impact information on SERPINF1

• In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia [5].
• Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis [5].
• The amount of inhibitory PEDF produced by retinal cells was positively correlated with oxygen concentrations, suggesting that its loss plays a permissive role in ischemia-driven retinal neovascularization [6].
• These results suggest that PEDF may be of therapeutic use, especially in retinopathies where pathological neovascularization compromises vision and leads to blindness [6].
• PEDF: bridging neurovascular interactions in the stem cell niche [7].

Chemical compound and disease context of SERPINF1

• In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes [8].
• In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney [9].
• Since Ang II-type 1 receptor interaction could contribute to exacerbation of diabetic retinopathy by downregulating pigment epithelium-derived factor (PEDF) gene expression in ECs, we examined here whether azelnidipine inhibited the Ang II-induced reactive oxygen species (ROS) generation and subsequent PEDF gene suppression in microvascular ECs [10].
• Upregulation of PEDF by azelnidipine may become a therapeutic target for the treatment of diabetic retinopathy associated with hypertension [10].
• Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, decreased retinal levels of 8-OHdG and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats [11].

Biological context of SERPINF1

• PEDF induces apoptosis in human endothelial cells by activating p38 MAP kinase dependent cleavage of multiple caspases [12].
• Cultured pigment epithelial cells of the fetal human retina secrete a protein, pigment epithelium-derived factor (PEDF), that induces a neuronal phenotype in cultured human retinoblastoma cells [13].
• Amino acid and DNA sequence data demonstrate that PEDF belongs to the serine protease inhibitor (serpin) family [13].
• We found that both CK2 and PKA phosphorylations of PEDF markedly affect its physiologic function [14].
• Moreover, intratumoral injection of a PEDF-expressing plasmid in athymic mouse models caused significant inhibition of preestablished tumor growth [15].

Anatomical context of SERPINF1

• Effects of triamcinolone on the expression of VEGF and PEDF in human retinal pigment epithelial and human umbilical vein endothelial cells [16].
• There was no significant difference in immunostaining intensity and localization of VEGF and PEDF in aged control choroids [2].
• PURPOSE: To investigate whether triamcinolone acetonide (TA) affects the expression of vascular endothelial growth factor (VEGF) and pigment epithelial derived factor (PEDF) in human retinal pigment epithelium (ARPE19) and human umbilical vein endothelial (HUVE) cells [16].
• Study the time course of the effects of TA on VEGF and PEDF expressions in cultured cells [16].
• In AMD, PEDF was significantly lower in RPE cells, RPE basal lamina, Bruch's membrane and choroidal stroma [2].

Associations of SERPINF1 with chemical compounds

• Pigment epithelium-derived factor (PEDF) is a multiple functional protein, coded by the serine proteinase inhibitor, clade F, member 1 (SERPINF1) gene, which has both anti-angiogenic activity and neurotrophic activity at the same time [17].
• The structure revealed the organization of possible receptor and heparin-binding sites, and showed that, unlike any other previously characterized serpin, PEDF has a striking asymmetric charge distribution that might be of functional importance [18].
• The PEDF gene contains a typical signal-peptide sequence, initiator methionine codon, and polyadenylylation signal and matches the size of other members of the serpin superfamily (e.g., alpha 1-antitrypsin) [13].
• However, treatment of PEDF with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide abolished it, implicating the PEDF aspartic and/or glutamic acid residues in its interaction with collagen I [19].
• Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22(phox) and gp91(phox), membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8-hydroxydeoxyguanosine [20].

Regulatory relationships of SERPINF1

• PEDF mRNA and protein expression was downregulated by neutralizing antibody against VEGF in differentiated human RPE cells [21].
• Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF [22].
• This suggested that TGF-beta 1 might regulate PEDF expression [23].
• The pyroglutamate residue may regulate the activity of PEDF analogously to the manner in which it regulates thyrotropin-releasing hormone [24].
• We, along with others, have recently found that PEDF could inhibit growth of melanoma and hepatocellular carcinoma in nude mice through its anti-angiogenic effects on tumor endothelial cells [25].

Other interactions of SERPINF1

• VEGFR-1 neutralization decreased PEDF mRNA and protein expression whereas anti-VEGFR-2 antibody had no effect [21].
• Addition of placenta growth factor (PlGF) restored PEDF expression in the presence of anti-VEGF antibody [21].
• CONCLUSIONS: TA reduces the expression of VEGF but increases the expression of PEDF in ARPE19 and HUVE cells [16].
• We provide evidence that induction of apoptosis by PEDF is associated with activation of p38 followed by cleavage of caspases 3, 8, and 9 by treatment with PEDF, and PEDF's actions are caspase dependent [12].
• However, PEDF immunoreactivity was significantly lower in RPE cells (p=0.0073), RPE basal lamina (p=0.0141), Bruch's membrane (p<0.0001), and choroidal stroma (p=0.0161) of AMD choroids [2].

Analytical, diagnostic and therapeutic context of SERPINF1

• Concurrently, the protein levels of VEGF and PEDF in ARPE cells were detected with ELISA [16].
• Tissues were cryopreserved and streptavidin alkaline phosphatase immunohistochemistry was performed with rabbit polyclonal anti-human VEGF and rabbit polyclonal anti-human PEDF antibodies [2].
• RESULTS: Real-time RT-PCR showed TA affected a 0.5 fold decrease in VEGF(165) level and about a 2.5 fold increase in PEDF level at both TA concentrations [16].
• Western blot analysis confirmed that the average PEDF level in pterygia was drastically lower than those in normal corneal and conjunctival tissues, respectively [26].
• Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF [3].

References