Serum Pigment Epithelium-derived Factor Research Articles

Predictive Value of Serum Vascular Endothelial Growth Factor and Pigment Epithelium-derived Factor in Ovarian Hyperstimulation Syndrome

Objective To explore whether the serum concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) could serve as the predictors of ovarian hyperstimulation syndrome (OHSS) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Enzyme-linked immunoadsordent assay (ELISA) was employed to measure the serum concentrations of VEGF and PEDF on the day of hCG administration, oocyte retrieval and embryo transfer, respectively. Based on OHSS classification of the criteria of Golan, 85 patients were divided into three groups. Patients in group A (n=10) showed symptoms of severe OHSS and patients in group B (n=13) suffered from moderate OHSS. The control group (group C, n=62) contained patients without symptoms of OHSS as well as patients with mild OHSS. Results In groups A, B and C, serum concentrations of PEDF on the day of hCG administration (h-PEDF) (166.54 ± 102.81 pg/ml, 159.45 ± 136.77 pg/ml, 172.05 ± 170.95 pg/ml, P=0.48), oocyte retrieval (o-PEDF) (176.91 ± 103.37 pg/ml, 122.52 ± 92.54 pg/ml, 179.82 ± 177.47 pg/ml, P=0.27) and embryo transfer (e-PEDF) (169.02 ± 240.08 pg/ml, 136.80 ± 139.21 pg/ml, 157.38 ± 222.54 pg/ml, P=0.95), h-VEGF (175.55 ± 103.54 pg/ml, 218.84 ± 179.70 pg/ml, 153.39 ± 145.06 pg/ml, P=0.36) and o-VEGF (171.93 ± 128.55 pg/ml, 220.36 ± 149.82 pg/ml, 138.74 ± 139.30 pg/ml, P=0.15) showed no significant differences. There was a statistical difference in serum concentration of e-VEGF between group A (197.04 ± 156.63 pg/ml) and group C (110.69 ± 49.55 pg/ml) (P=0.008). The serum level of estradiol showed a positive correlation with the count of large follicles (r=0.744). The ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF were calculated and showed a clear difference among groups A, B and C (4.04 ± 3.39, 2.10 ± 2.14, 1.05 ± 4.80, P Conclusion While neither serum concentrations of VEGF nor PEDF can be used as an OHSS predictor, the ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF may have great predictive value.

Serum levels of pigment epithelium-derived factor (PEDF) are independently associated with procollagen III N-terminal peptide levels in patients with nonalcoholic fatty liver disease

ObjectivesPigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex anti-oxidative, anti-fibrotic, and anti-inflammatory properties, thus being involved in cardiometabolic disorders. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome as well. However, the pathophysiological role of PEDF in NAFLD remains largely unknown. We studied here the relationship between serum PEDF levels and various clinical markers of NAFLD in humans. Design and methodsThe study involved 194 biopsy-proven NAFLD patients (102 male and 92 female) with a mean age of 51.3±13.8years. We examined which anthropometric, metabolic and inflammatory variables, and liver steatosis and fibrosis markers are independently associated with serum levels of PEDF. ResultsMean serum levels of PEDF were 16.4±5.7μg/mL. Univariate analysis revealed that age (inversely), male, body mass index, waist circumference, numbers of white blood cells and platelets, aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, glycated hemoglobin, uric acid, procollagen type III N-terminal peptide (P-III-P), subcutaneous fat areas, visceral fat areas and liver to spleen density ratio in computed tomography, the presence of diabetes and medication for hyperlipidemia were significantly associated with serum levels of PEDF. In multiple stepwise regression analysis, age (p<0.01, inversely), male (p<0.05), waist circumference (p<0.01), white blood cell number (p<0.05), P-III-P (p<0.05), and the presence of diabetes (p<0.05) and medication for hyperlipidemia (p<0.01), were independently correlated to serum levels of PEDF (R2=0.285). ConclusionsThe present study reveals that serum levels of PEDF are independently associated with P-III-P levels, suggesting that PEDF level is a novel biomarker of liver fibrosis in patients with NAFLD.

Lack of Circulating Pigment Epithelium-Derived Factor Is a Marker of Osteogenesis Imperfecta Type VI

Osteogenesis imperfecta (OI) type VI is a rare autosomal recessive bone fragility disorder that is caused by inactivating mutations in SERPINF1, the gene that encodes pigment-epithelium derived factor (PEDF). Determining PEDF serum levels might facilitate the diagnosis of OI type VI. The objective of the study was to assess whether lack of circulating PEDF is a specific marker of OI type VI and to evaluate whether PEDF serum levels are influenced by other metabolic bone diseases. Serum PEDF concentrations were measured in 12 patients with OI type VI (aged 2.7-31 yr) as well as in 96 children and adolescents with OI types I, III, and IV; in 26 young patients with hypophosphatemic rickets; and in 19 healthy controls. Circulating PEDF was undetectable in all 12 patients with OI type VI but was measurable for the other 141 study participants. No significant differences in serum PEDF concentrations were found between the diagnostic groups other than OI type VI. Treatment with bisphosphonates (in OI types I, III, and IV) and with phosphate and calcitriol (in hypophosphatemic rickets) did not have a detectable influence on serum PEDF. In patients with OI types I, III, and IV, serum creatinine, body mass index z-score, and OI severity were significant predictors of PEDF serum levels. Determining PEDF serum concentration helps to diagnose OI type VI but does not seem to provide information on the activity of bone turnover or mineralization.

Serum pigment epithelium-derived factor levels are independently associated with decreased number of circulating endothelial progenitor cells in healthy non-smokers

Pigment epithelium-derived factor (PEDF), a glycoprotein that belongs to the superfamily of serine protease inhibitors, was first purified from conditioned medium of human retinal pigment epithelial cells with a potent neuronal differentiating activity [ [1] Tombran-Tink J. Chader C.G. Johnson L.V. PEDF: pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res. 1991; 53: 411-414 Google Scholar ]. Recently, PEDF has been shown to be the most potent inhibitor of angiogenesis in the mammalian eye [ 2 Dawson D.W. Volpert O.V. Gillis P. et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999; 285: 245-248 Google Scholar , 3 Duh E.J. Yang H.S. Suzuma I. et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci. 2002; 43: 821-829 Google Scholar ]. Indeed, PEDF not only inhibits retinal endothelial cell growth and migration, but also suppresses ischemia-induced retinal neovascularization [ 2 Dawson D.W. Volpert O.V. Gillis P. et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999; 285: 245-248 Google Scholar , 3 Duh E.J. Yang H.S. Suzuma I. et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci. 2002; 43: 821-829 Google Scholar ]. Moreover, we have found that PEDF prevents vascular remodeling after balloon angioplasty and improves cardiac function in a rat model of acute myocardial infarction [ 4 Nakamura K. Yamagishi S. Matsui T. et al. Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation. Am J Pathol. 2007; 170: 2159-2170 Google Scholar , 5 Ueda S. Yamagishi S. Matsui T. Jinnouchi Y. Imaizumi T. Administration of pigment epithelium-derived factor inhibits left ventricular remodeling and improves cardiac function in rats with acute myocardial infarction. Am J Pathol. 2011; 178: 591-598 Google Scholar ]. These observations suggest that PEDF may also exert beneficial effects on ischemic heart disease as well as atherosclerosis.

Insulin resistance is associated with elevated serum pigment epithelium–derived factor (PEDF) levels in morbidly obese patients

Obesity is a significant risk factor for developing diabetes. Pigment epithelium-derived factor (PEDF) has been identified by experimental and clinical studies as both a causative and counter-regulatory factor in the metabolic syndrome. We set out to determine whether serum PEDF levels correlated with the degree of insulin resistance in morbidly obese patients. Sera from 53 patients who were evaluated prior to gastric bypass surgery were analyzed for PEDF levels using a commercial ELISA. None of the patients were on diabetes medications prior to enrollment. Baseline data included BMI, serum glucose and insulin, and homeostasis model assessment (HOMA) scores. Patients were stratified based on HOMA score and glucose levels into three groups: insulin sensitive (IS): HOMA <2 and glucose <126; insulin resistant (IR): HOMA >2 and glucose ≤126; and diabetes mellitus (DM): HOMA >2 and glucose >126. Pre- and post-gastric bypass sera from 12 patients were obtained for serial assessment of metabolic parameters and PEDF levels. PEDF secretion was assessed in primary human hepatocytes, HCC cells, and cultured adipocytes in the absence and presence of high glucose media. No significant differences in age, gender, and BMI were found among the three groups. PEDF levels were similar between IR patients and the other groups, but were significantly higher in DM compared to IS patients (p = 0.01). Serum PEDF in individual patients declined significantly after gastric bypass (p = 0.006). High glucose media led to significantly higher PEDF release by human hepatocytes in vitro (p = 0.016). These data demonstrate that serum PEDF concentrations better relate to insulin resistance than to adiposity and suggest that PEDF expression is closely linked to the development of insulin resistance.

Reduced Levels of Serum Pigment Epithelium-Derived Factor in Women With Endometriosis

The authors previously demonstrated decreased levels of pigment epithelium-derived factor (PEDF) in peritoneal fluid of women with endometriosis compared to women without endometriosis. Here, the authors determine whether women with endometriosis have altered levels of PEDF in serum. Peripheral blood samples were collected from 71 women with and without endometriosis (n = 43 and 28, respectively) before laparoscopic surgery. Concentrations of serum PEDF were measured by enzyme-linked immunosorbent assay. We detected lower levels of serum PEDF in women with endometriosis (16.3 ± 6.6 ng/mL) than in those without endometriosis (24.5 ± 7.3 ng/mL; P < .001). In women with endometriosis, the concentrations of serum PEDF were significantly lower in women with pain (n = 11, 12.6 ± 7.1 ng/mL) compared to women without pain (n = 32, 17.5 ± 6.0 ng/mL; P < .05). However, the concentrations of serum PEDF did not correlate with disease stage or site or infertility. In addition, the concentrations of serum PEDF did not show any difference in the phase of the cycle in either group. Our results suggest that reduced levels of serum PEDF in women with endometriosis and disease-related pain may play a role in the pathogenesis of this disease.

Pigment Epithelium-Derived Factor

Pigment epithelium-derived factor (PEDF), an adipokine, is a regulator of oxidative stress, inflammation, angiogenesis, and insulin sensitivity. Contrary to animal and cell culture data, inhibition of the sympathoadrenal system does not affect serum PEDF in humans. However, during acute beta-adrenergic receptor stimulation serum PEDF concentration is decreased. PEDF may be involved in cross talk between adipose tissue and skeletal muscle.

Serum pigment epithelium-derived factor levels are increased in patients with biopsy-proven nonalcoholic fatty liver disease and independently associated with liver steatosis

BackgroundIncreased serum concentrations of pigment epithelium-derived factor (PEDF) have been linked to the metabolic syndrome in the general population. However, the relationship between serum PEDF and nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, remains unknown. MethodsWe assayed serum PEDF levels in 156 patients with biopsy-proven NAFLD and 103 nonsteatotic control subjects who were matched for age and sex. The association between levels of PEDF and clinical, biochemical, and histological phenotypes was examined. ResultsNAFLD patients had significantly higher serum PEDF levels (1.97±0.50μg/mL) than control subjects (1.51±0.49μg/mL, Student's t test, P<0.001). Multivariable-adjusted stepwise regression analysis showed that PEDF ([beta]=0.32, t=3.13, P=0.002) and triglycerides ([beta]=0.22, t=2.23, P=0.02) were, in the order they entered into the model, the main independent predictors of steatosis scores in our patients with NAFLD. ConclusionsSerum PEDF levels are significantly increased in patients with biopsy-proven NAFLD and are associated with liver steatosis independently of traditional risk factors.

Effect of weight loss on serum pigment epithelium-derived factor levels

Cumulating evidence suggests that the broadly acting neurotrophic pigment epithelium-derived factor is associated with visceral adiposity, the metabolic syndrome, diabetes and exerts beneficial effects on atherosclerosis. To further elucidate the relationship between pigment epithelium-derived factor and metabolic perturbations characteristic of obesity, we examined the effect of pronounced weight loss on serum levels of pigment epithelium-derived factor. Thirty-six severely obese adults were examined before and 18 months after bariatric surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters by standard methods, pro-inflammatory biomarkers and serum pigment epithelium-derived factor levels by enzyme-linked immunosorbent assay. Bariatric surgery resulted in a mean body mass index (BMI) reduction of 9·0 ± 5·0 kg m(-2) and concomitant improvements in glucose homoeostasis and lipid profile. Pigment epithelium-derived factor serum levels decreased from a median 11·0 μg mL(-1) (interquartile range: 3·8) to 9·2 μg mL(-1) (interquartile range: 4·5) (P < 0·0001). In univariate analysis, relative change in pigment epithelium-derived factor levels was significantly associated with change in weight, BMI, fat mass, visceral fat diameter, insulin, homoeostasis model for insulin resistance, triglyceride and leptin levels (all r > 0·370, P < 0·05). No associations were observed for C-reactive protein, interleukin-6 or tumour necrosis factor alpha. After adjustment for age, sex and smoking status, associations remained significant. The beneficial effects of bariatric surgery-induced pronounced weight loss on glucose homoeostasis may partially be attributable to visceral adipose tissue reduction and concomitantly decreasing pigment epithelium-derived factor concentrations.

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-week-old Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 μg PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-β and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.

Serum Pigment Epithelium-Derived Factor Is Elevated in Women with Polycystic Ovary Syndrome and Correlates with Insulin Resistance

Serum pigment epithelium-derived factor (PEDF) is highly expressed in adipose tissue and plays an important role in insulin resistance (IR). However, there are no data on serum PEDF levels and their relationship with IR in polycystic ovary syndrome (PCOS) women. To quantitate serum PEDF levels and examine their relationship with IR in women with PCOS. Ninety-six PCOS women and 63 healthy age-matched controls were recruited. Ninety-six PCOS women and 20 controls underwent hyperinsulinemic-euglycemic clamp to assess their insulin sensitivity, which was expressed as M value. IR was also estimated by homeostasis model assessment 2 (HOMA2-IR). The study was performed at a clinical research center. PCOS women had lower M value and higher HOMA2-IR as compared with controls. Serum PEDF levels were much higher in PCOS women than in controls (5.45 ± 1.85 vs. 3.97 ± 0.98 μg/ml, P < 0.01). Spearman correlation analysis showed that in PCOS women, PEDF positively correlated with body mass index, waist circumference, HOMA2-IR, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and systolic blood pressure and negatively correlated with M value and high-density lipoprotein cholesterol. Multiple linear regression analysis revealed that in PCOS women, after adjustment for body mass index, systolic blood pressure, and serum lipids (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), PEDF was still associated with M value or HOMA2-IR. The serum PEDF level is elevated in women with PCOS and is associated with IR. PEDF may play a role in the pathogenesis of IR in PCOS.

Development of Enzyme-Linked Immunosorbent Assay System for PEDF and its Clinical Utility

Pigment epithelium-derived factor (PEDF) is reported to play a protective role against diabetic vascular complications through its anti-oxidative properties. However, since a commercially available kit is not suitable for measurement of serum PEDF in humans, kinetics and regulation of serum PEDF are not known in these devastating disorders. Therefore, we developed a simple, specific and reliable method for measurement of serum PEDF in humans using a competitive enzyme-linked immunosorbent assay (ELISA) system. Assay linearity was shown intact with 50~300-fold dilution of urea-pretreated serum by phosphate-buffered saline. The recovery ratio of added recombinant human PEDF in serum was 94.2 +/- 1.7 %. Inter- and intra-assay coefficient of variations of the ELISA were 4.7 and 7.3 %, respectively. When we measured serum PEDF levels in a general population, PEDF levels were elevated in proportion to the accumulation of the number of the components of the metabolic syndrome. Further, the percent changes in serum levels of PEDF during 1-year observational periods were positively correlated with those of body mass index (BMI) in patients with type 2 diabetes. In addition, PEDF mRNA levels in cultured adipocytes were increased in parallel to the BMI values of subjects from which adipocytes were derived, especially in omental adipocytes. These observations suggest that PEDF is generated from adipose tissues and could be increased as a counter-system against vascular cell damage in humans. PEDF may be one of the useful biomarkers for vascular injury in high-risk patients.

PEDF and Septic Shock

Septic shock is one of the leading causes of morbidity and mortality. Endotoxin plays an important role in the pathogenesis of septic shock. Lack of clinical success with anti-endotoxin or anti-cytokine therapies has shifted interest to extracorporeal therapies to reduce circulating levels of various mediators for septic shock patients. Polymyxin B -immobilized polystyrene fiber (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption. Since 1994, PMX-F column has been available in Japan, and many investigators have reported that PMX-F treatment is safe and effective in patients with septic shock. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. PEDF induces macrophages apoptosis and necrosis through the activation of peroxisome proliferator-activated receptor-gamma by which PEDF could modulate inflammatory reactions in septic shock. Further, given the fact that PEDF possesses anti-oxidative and anti-inflammatory properties in vivo, serum PEDF level may be a biomarker of septic shock. However, little is known about the relationship between serum level of PEDF and inflammatory biomarkers such as endotoxin and high mobility group box 1 (HMGB1) in septic shock and the effects of PMX-F treatment on these markers. This review aims to provide current knowledge about the pathogenesis of septic shock and the clinical utility of PMX-F treatment. We also discuss here the pathophysiological role of PEDF in this devastating disorder.

Positive Association of Serum Levels of Pigment Epithelium-Derived Factor with High-Sensitivity C-Reactive Protein in Apparently Healthy Unmedicated Subjects

Pigment epithelium-derived factor (PEDF), a glycoprotein with neuronal differentiating activity, possesses anti-inflammatory properties both in cell culture and animal models. However, the relationship between serum levels of PEDF and high-sensitivity C-reactive protein (hs-CRP), one of the representative biomarkers for inflammation in humans, is largely unknown. This study investigated whether serum PEDF levels were associated with hs-CRP in 120 apparently healthy unmedicated Japanese subjects (93 males, 27 females; mean age 58.0 years). All subjects underwent a complete history and physical examination, including blood chemistries, anthropometric and metabolic variables. Multiple regression analysis found that serum hs-CRP, creatinine and triglyceride levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) and body mass index were significantly and independently associated with serum PEDF levels. It is concluded that, serum levels of PEDF are associated with serum levels of hs-CRP independently of anthropometric, metabolic and renal function variables. The results also suggest that serum PEDF levels may be elevated as a counter-system against subclinical inflammation.

Pigment Epithelium-Derived Factor Inhibits Lysosomal Degradation of Bcl-xL and Apoptosis in HepG2 cells

Pigment epithelium-derived factor (PEDF) has several biological actions on tumor cells, but its effects are cell-type dependent. The aim of this study was to examine the pathophysiological role of PEDF in hepatocellular carcinoma (HCC). PEDF expression was examined in various hepatoma cell lines and human HCC tissues, and was seen in various hepatoma cell lines including HepG2 cells. In human HCC tissues, PEDF expression was higher than in adjacent non-HCC tissues. In addition, serum PEDF levels were higher in HCC patients than in non-HCC patients, and curative treatment of HCC caused significant reductions in serum PEDF levels compared with pretreatment levels. In vitro experiments, camptothecin (CPT) was used to induce apoptosis and the effect of PEDF was investigated by knockdown of the PEDF gene in CPT-treated HepG2 cells. Knockdown of the PEDF gene enhanced CPT-induced apoptosis, simultaneously down-regulating Bcl-xL expression in HepG2 cells. Expression of apoptosis-related molecules and effects of bafilomycin A1 on CPT-induced apoptosis were also examined in PEDF gene knockdown HepG2 cells. Treatment with bafilomycin A1 suppressed CPT-induced decreases in Bcl-xL expression and increases in apoptosis in PEDF gene knockdown HepG2 cells. PEDF may, therefore, exert anti-apoptotic effects through inhibition of lysosomal degradation of Bcl-xL in CPT-treated HepG2 cells.

Positive association of circulating levels of advanced glycation end products (AGEs) with pigment epithelium-derived factor (PEDF) in a general population

We have recently found that serum levels of pigment epithelium-derived factor (PEDF), a glycoprotein with anti-oxidative and anti-inflammatory properties, are elevated in proportion to the accumulation of the number of the components of the metabolic syndrome. Since formation and accumulation of advanced glycation end products (AGEs) progress under the metabolic syndrome and that PEDF could inhibit the AGE-elicited tissue damage, it is conceivable that PEDF levels may be increased as a counter-system against AGEs in patients with the metabolic syndrome. However, correlation between circulating levels of AGEs and PEDF in humans remains to be elucidated. In this study, we investigated the relationship between serum AGE and PEDF levels in a general population and examined the effects of AGEs on PEDF gene expression in vitro. One hundred ninety-six Japanese subjects in a general population underwent a complete history and physical examination, determination of blood chemistries, including serum levels of AGEs and PEDF. In multiple regression analyses, creatinine, body mass index, triglycerides, AGEs and insulin were independently correlated with serum PEDF levels. AGEs dose-dependently increased PEDF gene expression in cultured adipocytes and liver cells. Our present study demonstrated first that circulating AGEs were one of the independent correlates of serum levels of PEDF. Adipose tissue and liver may be target organs for the AGE-induced PEDF overexpression in humans. Serum PEDF levels may be elevated in response to circulating AGEs as a counter-system against the AGE-elicited tissue damage.

Serum PEDF Levels Are Decreased in a Spontaneous Animal Model for Human Autoimmune Uveitis

Identification of biomarkers is of critical relevance toward improving diagnosis and therapy of autoimmune disorders. Serum markers are a desirable choice as sera are easily accessible and the development of assays for routine clinical detection prompts feasible. Autoimmune uveitis, a recurrent disease affecting the eye, is characterized by returning inflammatory attacks of the inner eye followed by variable periods of quiescent stages. Spontaneous equine recurrent uveitis (ERU) is the equine equivalent and serves as a model for the human disease. To identify potential biomarker candidates, we first systematically compared the proteomes of individual ERU cases with healthy controls by proteomic profiling using 2-D difference-gel-electrophoresis (2-D DIGE) followed by tandem mass spectrometry. A total of seven differentially expressed proteins were identified. Besides the upregulation of IgG and the significant lower expression of albumin, Antithrombin III, and Vitamin D binding protein, we found complement components C1q and C4, to be downregulated in uveitic state. Interestingly, Pigment epithelium-derived factor (PEDF), a marker already detected by 2DE differential proteome analysis in ERU target tissues, vitreous and retina, was found to be also significantly downregulated in sera. The lower expression of PEDF in sera of horses with uveitis could be verified in a cohort of 116 ERU cases and 115 healthy controls. Our findings of a significant lower PEDF expression in ERU cases also in the periphery of the eye proves PEDF as a promising uveitis biomarker.

Serum levels of pigment epithelium-derived factor (PEDF) are an independent determinant of insulin resistance in patients with essential hypertension

We have previously found that serum level of pigment epithelium-derived factor (PEDF) is increased in proportion to the accumulation of the number of components of metabolic syndrome in general population. However, the link between PEDF and insulin resistance in hypertensive patients remains unclear. We investigated here whether serum PEDF level was associated with insulin resistance in hypertensive patients. Ninety-seven consecutive outpatients with essential hypertension underwent a complete history and physical examination, determination of blood chemistries, including serum PEDF. In multiple regression analyses, BMI, age (inversely) and PEDF were independently correlated with homeostasis model assessment of insulin resistance (HOMA-IR). When age- and sex-adjusted PEDF levels were stratified by HOMA-IR tertiles, a linear and significant trend was observed. These results demonstrated that serum level of PEDF was an independent determinant of HOMA-IR in patients with essential hypertension. PEDF may play a role in insulin resistance in hypertensive patients.

Serum levels of pigment epithelium‐derived factor (PEDF) are positively associated with visceral adiposity in Japanese patients with type 2 diabetes

Pigment epithelium-derived factor (PEDF) inhibits endothelial cell injury. Further, serum levels of PEDF are elevated in the metabolic syndrome. These observations suggest that PEDF may be elevated as a counter-system against vascular cell damage in the metabolic syndrome. However, little is known about the regulation of PEDF in patients with diabetes. In order to clarify the determinants of serum PEDF, here, we examined the relationship between the 1-year changes in PEDF levels and those in anthropometric and metabolic variables in type 2 diabetic patients. Eighty-six consecutive outpatients with type 2 diabetes underwent a complete history and physical examination, determination of blood chemistries, and serum levels of PEDF at baseline and 1 year after. PEDF gene expression in cultured subcutaneous or omental adipocytes were analysed by quantitative real-time reverse transcription-polymerase chain reactions. Multiple regression analyses revealed that waist circumference, triglycerides, creatinine, and TNF-alpha were independently associated with PEDF. Further, the percent changes in serum levels of PEDF during 1-year observational periods were positively correlated with those of BMI. In addition, PEDF mRNA levels in cultured adipocytes were increased in parallel to the BMI values of subjects from whom adipocytes were derived, especially in omental adipocytes. These results demonstrated that serum levels of PEDF were positively associated with metabolic components and TNF-alpha in Japanese patients with type 2 diabetes. Our present study suggests that PEDF may be generated from adipose tissues and play some role in visceral obesity in type 2 diabetic patients.

Serum level of pigment epithelium derived factor (PEDF) is an independent determinant of resting heart rate in Japanese subjects

We have recently found that serum level of pigment epithelium derived factor (PEDF) is significantly increased in proportion to the accumulation of the number of the components of the metabolic syndrome. Although high heart rate is also associated with metabolic risk factors for atherosclerosis, the correlation between serum level of PEDF and resting heart rate remains to be elucidated. In this study, we examined their relationship in Japanese outpatients. Four hundred two consecutive outpatients at Nakamura Clinic (141 male and 261 female; mean age 74.9 ± 9.9) underwent a complete history and physical examination, determination of blood chemistries and PEDF levels. In multiple regression analysis, smoking ( p = 0.003), use of β-blockers ( p = 0.010, inversely), presence of atrial fibrillation ( p = 0.014), PEDF ( p = 0.018) and glucose levels ( p = 0.033) were independently correlated to resting heart rate. Further, when mean serum PEDF levels were stratified by resting heart rates, a linear and significant trend ( p = 0.025) was observed. The present study demonstrated for the first time that serum level of PEDF was one of the independent determinants of resting heart rate in Japanese outpatients. PEDF may play some role in sympathetic nerve activity.