Angiogenic factors are elevated in overweight and obese individuals

BACKGROUND: Adipose tissue produces both vascular growth factors and inhibitors. Since obesity is associated with expansion of the capillary bed in regional adipose depots the balance between these factors may favor angiogenesis. OBJECTIVE: To investigate the relationship between body mass index and serum concentrations of vascular growth factors in human subjects. METHODS: Vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, soluble VEGF receptor-2 (sVEGFr2), hepatocyte growth factor (HGF), angiopoietin-2, angiogenin and endostatin concentrations were measured in serum collected from 58 lean (24 males, 34 female, mean BMI, 22.2+/-0.3) and 42 overweight and obese (16 males and 26 females, mean BMI, 33.5+/-1.2) subjects after an overnight fast. RESULTS: Sexual dimorphism was apparent in the serum concentrations of VEGF-C, VEFG-D and angiopoietin-2 with significantly higher levels in female compared to male subject. VEGF, VEGF-C, VEGF-D, soluble VEGF receptor-2, angiopoietin-2, angiogenin and endostatin but not HGF were significantly elevated in overweight and obese subjects. Positive correlations between BMI and the serum concentrations of VEGF-C, VEGF-D, sVEGF-R2, angiopoietin-2, angiogenin and endostatin were observed even after adjustment for gender and age. CONCLUSIONS: Increased levels of vascular growth factors as well as the angiogenesis inhibitor endostatin are present in overweight and obese subjects and may contribute to previously documented increased risk of metastatic disease in obese subjects with cancer.     

Decreased serum osteoprotegerin levels in patients with cardiac syndrome X

Receptor activator of nuclear factor KB (RANK) and osteoprotegerin (OPG) represent the ligand and decoy receptor, respectively, of a pleiotropic cytokine system that regulates bone metabolism and vascular biology. Several studies supported systemic microvascular abnormalities in patients with cardiac syndrome X (CSX). This study investigates serum OPG levels in healthy obese subjects and healthy lean controls affected by cardiac syndrome X. METHODS: We compared the OPG levels in 8 patients with cardiac syndrome X [2 males, 6 females; age: 46+/-6 yr; body mass index (BMI): 30+/-5 kg/m2] with 24 obese subjects (8 males, 16 females; age: 38+/-5 yr; BMI: 35+/-5 kg/m2) and 15 healthy lean controls (6 males, 9 females; age: 36+/-5 yr; BMI: 23+/-2 kg/m2; BMI<25kg/m2). RESULTS: Serum OPG levels in patients with cardiac syndrome X were lower than those in obese subjects and lean controls (11.45+/-8.36 pg/ml, 14.78+/-8.22 pg/ml, 19.24+/-6.96 pg/ml, respectively, cardiac syndrome X vs lean controls, p=0.039). CONCLUSIONS: Serum OPG levels are lower in patients with CSX. Further studies on the mechanisms of OPG in microangiopathy may help to evaluate the OPG system role as a marker for disease activity, prognosis and response to therapy in cardiovascular diseases.     

Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36

BACKGROUND: Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation. AIM: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. DESIGN: Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals. RESULTS: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects. CONCLUSION: Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.     

Serum retinol-binding protein 4 is reduced after weight loss in morbidly obese subjects

CONTEXT: Administration of retinol-binding protein 4 (RBP-4) impairs insulin sensitivity in animals, and elevated serum concentrations have been associated with insulin resistance in humans. OBJECTIVE: We have studied whether weight loss influences RBP-4. PATIENTS AND METHODS: Fasting serum concentrations of RBP-4 were measured before and 6 months after gastric banding surgery in 33 morbidly obese patients aged 40 +/- 11 yr with a body mass index (BMI) of 46 +/- 5 kg/m(2). Fourteen healthy subjects aged 29 +/- 5 yr with a BMI less than 25 kg/m(2) served as controls. To characterize the association of weight loss with central and peripheral appetite regulation, the signaling protein agouti-related protein (AGRP), the orexigenic hormone ghrelin, and its recently identified antagonist obestatin were determined. RESULTS: At baseline, RBP-4 levels were markedly higher in obese than in lean subjects (2.7 +/- 0.5 vs. 0.9 +/- 0.5 microg/ml; P < 0.001). In contrast, AGRP and obestatin were lower in obese subjects compared with lean controls (all P < 0.001). Six months after gastric banding, BMI was reduced to 40 +/- 5 kg/m(2), RBP-4 was reduced to 2.0 +/- 0.7 microg/ml, AGRP increased from 1.8 +/- 1.1 to 3.4 +/- 1.1 ng/ml, ghrelin increased from 93 +/- 58 to 131 +/- 70 pg/ml, and obestatin increased from 131 +/- 52 to 173 +/- 35 pg/ml (all P < 0.05). Individual changes of RBP-4 were associated with changes of BMI (r = 0.72), the homeostasis model assessment insulin resistance-index (r = 0.53), and total cholesterol (r = 0.42, for all P < 0.05). CONCLUSION: Reductions in circulating RBP-4 may contribute to improved insulin resistance in morbidly obese subjects after weight loss. This is accompanied by favorable changes in appetite-regulating hormones, which might support the sustained weight loss after obesity surgery.     

Serum concentrations of nitric oxide, tumor necrosis factor (TNF)-alpha and TNF soluble receptors in women with overweight and obesity

The aims of the present study was to examine how overweight and obesity affect serum concentrations nitric oxide (NO) metabolites and to determine whether there is association between serum concentrations tumor necrosis factor (TNF)-alpha and TNF soluble receptors (sTNF-R) in subjects with overweight and obesity. The study groups involved 154 women: 102 obese (81 obese with body mass index [BMI] 30 to 40 kg/m2 and 21 obese with BMI > 40 kg/m2), 24 overweight patients, and 28 lean controls. Serum concentrations of NO metabolites and of TNF-alpha and its soluble receptors (sTNF-R1, sTNFR-2) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Serum concentration of insulin was measured by radioimmunoassay (RIA). Plasma glucose, cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglicerydes were determined by enzymatic procedure. Body composition was determined by impedance analysis using Bodystat (Douglas, British Isles). Serum concentrations of NO in the overweight group (35.1 +/- 12.1 micromol/L) and the obese groups with BMI 30 to 40 kg/m2 (32.8 +/- 9.3 micromol/L) and with BMI greater than 40 kg/m2 (33.3 +/- 8.5 micromol/L) were significantly higher when compared to controls (28.2 +/- 8.1 micromol/L): P < .05; P < .01, and P < .01, respectively. There was no difference in levels of NO between the overweight group and both obese groups. Serum concentration of TNF-alpha was also significantly higher in the group with overweight (6.5 +/- 3.1 pg/mL), in the obese group with BMI 30 to 40 kg/m2 (6.8 +/- 3.1 pg/mL), and in the obese group with BMI greater than 40 kg/m2 (7.4 +/- 2.6 pg/mL) when compared to controls (2.9 +/- 2.2 pg/mL): P < .00005; P < .00005, and P < .0000001, respectively. However, serum concentrations of sTNF-R1 and -R2 did not differ significantly between the overweight group, both obese groups, and controls. In conclusion, we observed increased serum concentrations of TNF-alpha and NO in overweight and obese women. It seems that there is an association between serum concentrations of TNF-alpha and NO; however, this relationship depends on the degree of obesity.     

Effects of obesity and weight loss on the expression of proteins involved in fatty acid metabolism in human adipose tissue

OBJECTIVE: Disturbances in adipocyte lipolysis in obesity may contribute to elevated circulating non-esterified fatty acid (NEFA) concentrations and insulin resistance. In experimental models, NEFA metabolism is influenced by adipocyte proteins such as adipocyte and keratinocyte lipid binding proteins (aP2/ALBP and mal1/KLBP) and fatty acid translocase (CD36). We investigated the effect of obesity and weight loss on the expression of these proteins in human subcutaneous adipose tissue. STUDY DESIGN AND SUBJECTS: Subcutaneous adipose tissue was obtained from 12 obese (body mass index (BMI) 42.4+/-1.6 kg/m(2)) and 12 lean (23.4+/-0.6 kg/m(2)) subjects. The obese subjects underwent gastric banding and biopsies were taken again after 2 y following a significant weight reduction (BMI 32.8+/-1.4 kg/m(2)). Adipose tissue proteins were quantified by Western blotting. RESULTS: Differential expression of ALBP, KLBP and CD36 was observed in lean and weight-reduced subjects compared with obese individuals. This resulted in a significantly lower ALBP/KLBP ratio in lean and weight-reduced individuals compared to obese subjects. Furthermore there was a significant influence of gender on this ratio. Moreover, the commonly used internal standard protein actin was expressed significantly higher in lean compared to obese individuals. CONCLUSION: The relative content of ALBP and KLBP in human adipose tissue changes with obesity, weight loss and gender indicating differential regulation. Differing responses in the expression patterns of adipose tissue proteins capable of binding NEFAs in response to weight changes suggest a potential importance in the development of obesity-associated complications.     

Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans

OBJECTIVE: Leptin plays a major role in the regulation of body weight. It circulates in both free and bound form. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. In the present study, we measured the soluble leptin receptor (SLR) levels in lean and obese humans. We investigated the relationship between plasma SLR levels, plasma leptin levels and the degree of obesity. We also examined whether SLR concentrations could be modulated by fat mass loss induced by a 3 month weight-reducing diet. SUBJECTS: A total of 112 obese (age 18-50 y; body mass index (BMI) 30-44 kg/m2; 23 men and 89 women), 38 overweight (age 19-48 y; BMI 25-29 kg/m2; 10 men and 28 women) and 63 lean (age 18-50 y; BMI 17-24 kg/m2; 16 men and 47 women) humans. MEASUREMENTS: A direct double monoclonal sandwich enzyme-linked immunosorbent assay (ELISA) was used for the quantitative measurement of the soluble human leptin receptor. Leptin was measured by radioimmunoassay (RIA). Body composition was assessed by biphotonic absorptiometry DEXA (dual energy X-ray absorptiometry). RESULTS: We observed that the SLR is present in human plasma (range 10-100 ng/ml). SLR levels were lower in obese and overweight than lean subjects (28.7+/-8.8, 40.2+/-14.9, 51.2+/-12.5 ng/ml, respectively) and were inversely correlated to leptin and percentage of body fat (r=-0.74 and r=-0.76; respectively; P<0.0001). The ratio of circulating leptin to SLR was strongly related to the percentage of body fat (r=0.91; P<0.0001). Interestingly a gender difference was observed in SLR levels, which were higher in obese and overweight men than in obese and overweight women. In obese subjects after a 3 month low-calorie diet, SLR levels increased in proportion to the decrease in fat mass. In the gel filtration profile, SLR coeluted exactly with the bound leptin fractions. CONCLUSION: Obesity, in humans is associated with decreasing levels of the circulating soluble leptin receptor (SLR). The relationship of SLR with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects.     

Relationship between serum tumor necrosis factor-alpha and insulin resistance in obese men with Type 2 diabetes mellitus

We analyzed serum concentrations of tumor necrosis factor-alpha (TNF-alpha) for their role in insulin resistance in 12 obese men with untreated Type 2 diabetes mellitus and in 6 age-and BMI-matched obese controls. Insulin resistance was expressed using the homeostasis model assessment (HOMA-R). Six of the patients were insulin-resistant (HOMA-R>5.0), while six were not (HOMA-R相似文献   

B-type natriuretic peptide levels in obese patients with advanced heart failure.

Although recent studies show that obesity, or elevated body mass index (BMI), is associated with lower levels of B-type natriuretic peptide (BNP), it is unknown whether BMI affects the prognostic value of BNP in heart failure (HF). This study confirms the relationship between high BMI and low BNP in patients with advanced systolic HF. Despite relatively lower levels of BNP in overweight and obesity, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality in HF at all levels of BMI.OBJECTIVES: This study aimed to examine the influence of obesity on the predictive value of the B-type natriuretic peptide (BNP) assay in heart failure (HF). BACKGROUND: Recent studies show that obesity, or elevated body mass index (BMI), is associated with lower circulating levels of BNP both in the general population and in patients with HF. METHODS: We analyzed data from 316 systolic HF (left ventricular ejection fraction [LVEF] < or =40%) patients [age, 53 +/- 13 years; mean LVEF, 24 +/- 7%; 48% ischemic] followed up at a university HF center. Patients were divided into categories of BMI: lean (BMI <25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI > or =30 kg/m2). RESULTS: The BNP levels were significantly lower in overweight and obese compared with lean patients (p = 0.0001); median BNP (interquartile range) for the lean (n = 131), overweight (n = 99), and obese (n = 86) groups was 747 (272 to 1,300), 380 (143 to 856), and 332 (118 to 617) pg/ml, respectively. In each BMI category, elevated BNP was significantly associated with worse symptoms and higher pulmonary capillary wedge pressure. Higher BNP was also a significant independent predictor of survival independent of BMI. Optimal BNP cutoff for prediction of death or urgent transplant in lean, overweight, and obese HF patients was 590, 471, and 342 pg/ml, respectively. CONCLUSIONS: Although BNP levels are relatively lower in overweight and obese HF patients, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality at all levels of BMI.     

Concentrations of hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor in pericardial fluid and plasma

Some angiogenic factors, including hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), have been reported to promote angiogenesis and improve myocardial perfusion in experimental models of ischemic heart disease. These factors are produced in various tissues, including myocardium. We measured the concentrations of HGF, bFGF, and VEGF by enzyme-linked immunosorbent assay in plasma and in pericardial fluid sampled during open heart surgery (12 patients with ischemic heart disease and 17 with nonischemic heart disease). HGF levels were significantly higher in plasma than in pericardial fluid (12.0 +/- 1.8 versus 0.26 +/- 0.04 ng/mL, P < 0.0001). On the other hand, bFGF levels were significantly higher in pericardial fluid than in plasma (243.5 +/- 50.9 versus 49.6 +/- 7.8 pg/mL, P = 0.009). VEGF levels were not significantly different between pericardial fluid and plasma (47.2 +/- 17.6 versus 24.5 +/- 3.6 pg/mL, P = 0.23). Concentrations of angiogenic factors in pericardial fluid and in plasma were not significantly different between patients with ischemic and nonischemic heart disease. These results suggest that the production, secretion, and kinetics of HGF, bFGF, and VEGF are different. These angiogenic factors may have different pathophysiologic roles.     

Serum resistin (FIZZ3) protein is increased in obese humans

The role of resistin in obesity and insulin resistance in humans is controversial. Therefore, resistin protein was quantitated by ELISA in serum of 27 lean [13 women/14 men, body mass index (BMI) 21.7 +/- 0.4 kg/m(2), age 33 +/- 2 yr] and 50 obese (37 women/13 men, BMI 49.8 +/- 1.5 kg/m(2), age 47 +/- 1 yr) subjects. There was more serum resistin protein in the obese (mean +/- SEM: 5.3 +/- 0.4 ng/ml; range 1.8-17.9) than lean subjects (3.6 +/- 0.4 ng/ml; range 1.5-9.9; P = 0.001). The elevation of serum resistin in obese humans was confirmed by Western blot as was expression of resistin protein in human adipose tissue and isolated adipocytes. There was a significant positive correlation between resistin and BMI (r = 0.37; P = 0.002). Multiple regression analysis with predictors BMI and resistin explained 25% of the variance in homeostasis model assessment of insulin resistance score. BMI was a significant predictor of insulin resistance (P = 0.0002), but resistin adjusted for BMI was not (P = 0.11). The data demonstrate that resistin protein is present in human adipose tissue and blood, and that there is significantly more resistin in the serum of obese subjects. Serum resistin is not a significant predictor of insulin resistance in humans.     

Acute hyperinsulinemia is associated with increased plasma adrenomedullin concentrations in uncomplicated obesity.

OBJECTIVE: Adrenomedullin (AM) is a potent hypotensive peptide which may be implicated in the insulin regulatory system. Acute hyperinsulinemia exerts no influence on plasma AM in normal subjects while no data on obese subjects has been reported. PURPOSE: The aim of the study was to investigate the effect of acute hyperinsulinemia on the plasma AM concentration in patients with uncomplicated obesity. RESEARCH METHODS: We measured the plasma AM levels in 23 obese subjects (BMI 41.9 +/- 9.8 kg/m2), 21 females and 2 males (mean age 31 +/- 7.2 years), before and during a euglycemic hyperinsulinemic clamp. The control group consisted of 43 healthy subjects (HS) (22 males and 21 females; mean age 38 +/- 12 years; BMI 23.3 +/- 3.2 kg/m2). RESULTS: Baseline plasma AM was found to be higher in obese subjects (20.4 +/- 8.4 pg/ml) than in normal subjects (11.3 +/- 0.8 pg/ml) (p < 0.001). A significant increase in the plasma AM levels was observed in obese subjects during acute hyperinsulinemia (from 20.4 +/- 8.4 pg/ml at 0 min to 26 +/- 8.9 pg/ml at 120 min, p < 0.02). Plasma AM concentrations were significantly correlated with insulin levels at 30 min (r = 0.44; p = 0.04) and 120 min (r = 0.40, p = 0.05) during the clamp. DISCUSSION: In conclusion, acute hyperinsulinemia induced a significant increase in the plasma levels of AM in uncomplicated obese subjects. Hyperinsulinemia may, at least in part, regulate levels of AM in obesity, explaining the high levels of the peptide in these subjects.     

Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients.

AIMS: The aim of the study was to analyse the role of tumour necrosis factor-alpha (TNF-alpha) in insulin resistance and endothelial dysfunction in patients with different types of obesity. PATIENTS AND METHODS: Fasting serum TNF-alpha immunoreactive concentration (enzyme-linked immunosorbent assay, ELISA) and bioactivity (L929 cell cytotoxicity assay), endothelin-1 and C-peptide levels (radioimmunoassay, RIA) were measured in 15 patients with android- and 13 patients with gynoid-type obesity and 15 lean healthy controls with normal glucose tolerance and blood pressure. RESULTS: Significantly (P<0.01) higher TNF-alpha concentration (8.92 +/- 0.44 pg/ml) and bioactivity (3.12 +/- 0.48 U/ml) were found in patients with android obesity as compared to patients with gynoid obesity (7.01 +/- 0.30 pg/ml, 0.97 +/- 0.11 U/ml) and to the lean controls (6.88 +/- 0.26 pg/ml, 0.88 +/- 0.08 U/ml). Serum endothelin-1 (5.38 +/- 0.30 pg/ml) and C-peptide levels (4.82 +/- 0.71 ng/ml) were also significantly higher (P < 0.01) in patients with android-type obesity than in controls (3.89 +/- 0.43 pg/ml, 1.46 +/- 0.25 ng/ml, respectively). In patients with gynoid-type obesity, only the C-peptide levels proved to be significantly higher (2.84 +/- 0.29 ng/ ml). Endothelin-1 levels, although were found to be slightly higher, did not differ statistically from in controls (4.56 +/- 0.31 pg/ml). There were significant positive linear correlations only in patients with android-type obesity between TNF-alpha, body mass index (BMI), serum endothelin-1 and C-peptide levels. CONCLUSIONS: TNF-alpha may be one of the factors contributing to insulin resistance and vascular dysfunction in patients with android obesity.     

IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin?

We have recently shown that human monocytic cells express functional leptin receptors and that leptin is capable of inducing the expression and secretion of the IL-1 receptor antagonist (IL-1Ra). Although IL-1Ra has anti-inflammatory and possibly anti-atherogenic properties, it has also been shown to antagonize the action of leptin at the hypothalamic level in rodents, thereby inducing leptin resistance. We have therefore examined whether IL-1Ra levels are increased in human hyperleptinemic conditions, such as obesity. To this end, we measured serum IL-1Ra levels in 20 morbidly obese nondiabetic subjects [body mass index (BMI), 45 +/- 6 kg/m(2); serum leptin, 52 +/- 20 ng/ml] as well as in 10 age- and sex-matched lean controls (BMI, 22 +/- 2 kg/m(2); serum leptin, 7 +/- 4 ng/ml). Serum IL-1Ra concentrations proved to be elevated 6.5-fold in the obese subjects, and they were positively correlated in a linear manner with the leptin levels (r(2) = 0.34; P = 0.01), although lean body mass (LBM) and the insulin resistance index were even better predictors of IL-1Ra levels (r(2) = 0.45 and 0.58, respectively; P < 0.01). Six months after 15 of the 20 obese subjects had undergone bypass surgery for their morbid obesity, their mean BMI and leptin levels decreased to 33 +/- 7 kg/m(2) and 18 plus minus 12 ng/ml, respectively. This change in leptin concentrations was associated with a significant reduction in IL-1Ra levels (P < 0.02). However, there was a better correlation between the decrease in IL-1Ra level and the change in LBM than with the reduction in leptin levels, indicating that leptin is not the sole determinant of circulating IL-1Ra in obesity. In summary, we demonstrate that IL-1Ra levels are highly elevated in human obesity and that its concentrations decrease after weight loss from bypass surgery. However, LBM and insulin resistance are better predictors of serum IL-1Ra concentrations than are leptin levels, suggesting that additional metabolic factors control the secretion of this cytokine antagonist. Although the immunological consequences of this alteration remain unknown, it is tempting to speculate that the obesity-related increase in IL-1Ra might contribute to the central resistance to leptin in obese patients, similar to the inhibition of the hypothalamic signaling of leptin by IL-1Ra in rodents.     

Circulating hepatocyte growth factor level but not basic fibroblast growth factor level is elevated in angiography-proven symptomatic peripheral artery disease

Circulating vasogenic factors may be up-regulated in response to ischemia to promote angiogenesis in patients with peripheral artery disease (PAD). Studies on this are limited in number and size, and results are inconsistent, especially regarding basic fibroblast growth factor (bFGF) level. From March 1999 to April 2004, all consecutive patients with lower limb PAD having serum samples at the time of intervention were recruited. The diameter of the primary PAD lesion had to be at least 70% stenotic at the lower limb artery. Control subjects, who underwent angiography, were free of PAD, coronary disease, and other major medical diseases. Serum samples were analyzed for circulating hepatocyte growth factor (HGF) and bFGF levels. Patients with PAD (n = 60) had higher circulating HGF levels (mean +/- SEM, 1,544 +/- 238 vs 970 +/- 129 pg/mL; P = .04) but similar bFGF distribution tertiles (P = .55) compared with control subjects (n = 30). Thirty-six patients with summed PAD lesion lengths exceeding 5 cm demonstrated a significantly higher circulating HGF level compared with control subjects (mean +/- SEM, 1,701 +/- 335 vs 970 +/- 129 pg/mL; P = .048). Patients with concurrent coronary artery disease tend to have a higher circulating HGF level (mean +/- SEM, 1,606 +/- 365 vs 970 +/- 129 pg/mL; P = .06) but not a higher bFGF level compared with control subjects. Circulating HGF level, but not bFGF level, is significantly elevated in patients with symptomatic angiographically documented PAD, especially in those with more extensive involvement.     

Effects of oxygen administration on the circulating vascular endothelial growth factor (VEGF) levels in patients with obstructive sleep apnea syndrome

OBJECTIVE: Repeated nocturnal hypoxia is implicated in the pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS). We hypothesized that circulating vascular endothelial growth factor (VEGF) levels are affected by nocturnal hypoxemia in patients with OSAS. METHODS: We examined the serum VEGF levels in patients with OSAS and in control subjects. We also tested the effects of oxygen or air administration on the subjects' VEGF levels. PATIENTS AND MATERIALS: Twenty-four OSAS patients (mean age 54.2 +/- 3.6 years) and 24 age-matched control subjects (53.2 +/- 3.6 years). Their serum samples were tested. RESULTS: Serum VEGF levels at 8:00 AM were significantly higher in OSAS patients than in controls (p<0.01). VEGF levels decreased from 515 +/- 31 (pg/ml) to 178 +/- 16 (pg/m) (p<0.01) in OSAS patients whose nocturnal hypoxemia was found to be improved by administration of 2 l/min of oxygen during the night. However, the administration of compressed air affected neither the VEGF level nor nocturnal oxygen desaturation in OSAS patients. CONCLUSION: These results indicate that circulating VEGF levels are elevated in OSAS patients, primarily due to nocturnal hypoxemia.     

Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects

Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 +/- 4 yr; body mass index (BMI), 25.4 +/- 4.3 kg/m(2)], 12 obese subjects (age, 54 +/- 8 yr; BMI, 33.0 +/- 2.5 kg/m(2)), and 22 obese subjects with type 2 diabetes (age, 59 +/- 7 yr; BMI, 34.0 +/- 2.4 kg/m(2)) were studied. Serum resistin concentrations were not different among nonobese (4.1 +/- 1.7 ng/ml), obese (4.2 +/- 1.6 ng/ml), and obese diabetic subjects (3.7 +/- 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = -0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P < 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.     

Hepatocyte growth factor and cardiovascular thrombosis in patients admitted to the intensive care unit.

BACKGROUND: Hepatocyte growth factor (HGF) has been reported as a marker of atherosclerosis and of thrombi synthesis, but the relationship between HGF and proven coronary thrombi has not been described. The aim of this study was to investigate this relationship in patients with chest pain. METHODS AND RESULTS: The study group comprised 107 patients with chest pain (61 acute myocardial infarction (AMI), 18 unstable angina, 15 stable angina, and 13 others; 65 males, 42 females; 66+/-11 years old). The presence of thrombi was evaluated by angiography, intravascular ultrasonography, angioscopy, and computed tomography. Serum HGF concentrations were measured using a new enzyme-linked immunosorbent assay. Serum HGF was significantly higher in the patients with AMI (335.0 +/-197.5 pg/ml), unstable angina (269.1+/-152.7 pg/ml), acute aortic dissection (320.3+/-116.5 pg/ml), and pulmonary thromboembolism (292.5+/-101.9 pg/ml), than in those with stable angina (171.2+/-56.1 pg/ml). Serum HGF concentration was also higher in those patients with proven thrombi than in those patients without (326.7+/-189.7 pg/ml vs 226.9+/-110.8 pg/ml). CONCLUSION: Increased serum HGF concentrations correlate with the presence of thrombi in patients with acute coronary syndrome, acute aortic dissection, and pulmonary thromboembolism.     

Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients.

OBJECTIVES: Our objectives were to compare angiogenesis soluble factor (ASF) levels in chronic hepatitis C (CHC) patients and healthy individuals, and to investigate potential associations between ASF levels and both histological and biochemical markers of disease progression. METHOD: Thirty-six patients (69% males) positive for HCV-RNA by PCR analysis were included in the study. All patients underwent liver biopsy before treatment. Serum levels of vascular endothelial growth factor (VEGF), soluble Flt-1 and Flk-1 receptors, placental growth factor (PlGF), angiopoietin-2 (Ang-2) and soluble Tie-2 receptor were determined by ELISA. Fifteen healthy subjects were used as controls. RESULTS: In comparison to healthy individuals, CHC patients showed significantly increased serum levels of proangiogenic factors PlGF (22 +/- 5 vs. 18 +/- 8 pg/ml; p < 0.05), Ang-2 (1265 +/- 385 vs. 833 +/- 346 pg/ml; p < 0.005) and sFlt-1 (95 +/- 22 vs. 72 +/- 14 pg/ml; p < 0.0001). Interestingly, in CHC patients serum levels of VEGF and Tie-2 correlated with grade of inflammation, PlGF correlated with stage of fibrosis, and Flt-1 and Flk-1 correlated with serum transaminase levels (p < 0.05 in all cases). CONCLUSIONS: CHC patients showed increased serum levels of ASF, and a significant correlation was shown between serum levels of selected ASFs and grade of inflammation, stage of fibrosis, and transaminase levels.