(Hypertension. 1999;34:568-573.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Early Upregulation of Endothelial Adhesion Molecules in Obese Hypertensive Men
From the University "La Sapienza," Cattedra di I Clinica Medica, Andrea Cesalpino Foundation (C.F., G.D., M.P., G.D.M.), Rome; and the University of L'Aquila, Departments of Experimental (C.B.) and Internal (M.V., A.S.) Medicine, L'Aquila, Italy.
Correspondence to Claudio Ferri, MD, University "La Sapienza," Fondazione Andrea Cesalpino, Cattedra di I Clinica Medica, Servizio Divisionale di Fisiopatologia dell'Ipertensione Arteriosa, 00161 Roma, Italy. E-mail clferri{at}axrma.uniroma1.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Upregulation of endothelial adhesion molecules is the earliest step of atherogenesis. Whether obesity induces endothelial adhesin upregulation is unknown. To address this topic, circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor (vWF) concentrations were evaluated in 22 obese hypertensive (51.4±4.6 years [mean±SD age]), 19 obese normotensive (50.6±3.8 years), 18 nonobese hypertensive (52.3±3.9 years), and 16 nonobese normotensive (52.4±3.5 years) men without other risk factors or overt atherosclerosis. All measurements were repeated in the obese subgroups after weight loss induced by 12 weeks of caloric restriction. Basal circulating VCAM-1 levels were similar between the 2 obese groups but were higher (P<0.0001) than in the 2 nonobese groups. No differences were found between nonobese hypertensives and normotensives. Serum low density lipoprotein cholesterol was weakly correlated with plasma soluble VCAM-1 levels in pooled, obese subjects (r=0.362, P=0.02). Plasma soluble adhesin and vWF concentrations decreased significantly after weight loss in obese hypertensives (VCAM-1 P=0.03, ICAM-1 P=0.004, E-selectin P<0.0001, and vWF P=0.003) and normotensives (VCAM-1 P=0.04, ICAM-1 P=0.003, E-selectin P<0.0001, and vWF P<0.0001). Body mass index was correlated with plasma E-selectin concentrations at baseline and after weight loss in obese hypertensives (r=0.501, P=0.018 and r=0.466, P=0.03, respectively) and obese normotensives (r=0.523, P=0.021 and r=0.460, P=0.05, respectively). In conclusion, our data show that obesity per se induces early endothelial activation in hypertensive and normotensive men. Weight loss counteracted endothelial activation in both obese hypertensive and normotensive men.
Key Words: hypertension • obesity • endothelium • adhesion molecules • risk factors
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Obesity increases the risk of cardiovascular death in adult subjects.1 Although cardiovascular risk factors2 are often present in obese subjects, obesity per se might favor the development of atherosclerosis.2 3 Cardiovascular diseases increase with body weight independent of other risk factors.3 Obesity and central body fat disposition have been correlated with a higher prevalence of cardiovascular death in low-risk subjects.4 The relative risk of cardiovascular death associated with an increment of 1 kg/m2 in body mass index (BMI) is 1.10 and 1.08 for adult men and women, respectively.1 Thus, although the influence of other risk factors such as low physical activity and excess alcohol intake2 cannot be excluded, obesity acts as an independent cardiovascular risk factor.
Upregulation of endothelial adhesins of the selectin family5 (E-selectin and P-selectin) and of the immunoglobulin superfamily6 [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)] allows the attachment of circulating cells to the endothelium and represents the initiating event in atherogenesis.7 8 Upregulation of adhesin genes leads to the expression of membrane-associated adhesins and release of their soluble forms. Thus, circulating soluble adhesin levels act as markers of in vivo adhesin expression.8 9 10 11 Accordingly, plasma soluble E-selectin concentrations were found to be elevated in conditions associated with increased risk for developing atherosclerosis, ie, type 2 diabetes12 13 and hypertension.14 Similarly, plasma soluble VCAM-1, ICAM-1, and E-selectin concentrations were found to be elevated in glucose-intolerant hypertensives.15 Augmented levels of circulating von Willebrand factor (vWF), a marker of in vivo endothelial damage,16 were found in nonatherosclerotic obese persons.17 Furthermore, circulating levels of endothelin-118 and tissue plasminogen activator-119 were increased while endothelium-dependent vasodilation20 was reduced in normotensive obese individuals.
Taken together, the above data support the concept that obesity per se might induce early endothelial activation in humans. In view of the possible relationship between such endothelial activation and obesity, we evaluated circulating soluble VCAM-1, ICAM-1, and E-selectin concentrations in low-risk, obese subjects who had no conditions known to affect circulating adhesin levels.11 Estrogen influence on soluble adhesins21 was excluded by studying a male population. Plasma soluble adhesin levels were assessed both before and after weight loss resulting from caloric restriction. To evaluate the influence of weight loss–related changes in blood pressure modifications, we also studied obese hypertensives before and after the same caloric restriction. Nonobese hypertensive and normotensive groups served as controls.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patient Recruitment
The study was conducted in 19 normotensive obese men (mean±SD age, 50.6±3.8 years) and 22 obese male outpatients with untreated essential hypertension (51.4±4.6 years). Most patients had participated in a previous study by our group,18 and we used previously collected, stored plasma samples for this study. After approval from our Ethics Committee, informed consent was obtained from the patients selected for being white, nonsmokers, and with a BMI >30 kg/m2.18 Glucose tolerance was normal, and serum cholesterol and triglycerides were <5.5 mmol/L and 1.8 mmol/L, respectively. In obese hypertensives and normotensives, supine diastolic blood pressure levels were 95 to 114 mm Hg and <90 mm Hg, respectively, on 4 different visits at 1-week intervals. Serum creatinine was <100 µmol/L, and albuminuria was <20 µg/min. Clinical and ultrasound examinations of neck and limb vessels were normal. Patients with an abnormal electrocardiogram, positive histories of angina or vascular diseases, or a parental history of vascular diseases before the age of 60 were excluded. Patients had no concomitant diseases, allergies, or recent acute infectious or inflammatory diseases.
After recruitment, the outpatients began a weight-maintaining diet for 1 week.18 Then, after an overnight fast, they were admitted to our unit at 8 AM. A forearm vein was cannulated, and after 1 hour in a supine position, venous blood samples for plasma adhesin and vWF assays were collected in prechilled tubes containing EDTA. Tubes were centrifuged at 3000 rpm and plasma aliquots were stored at -80°C until assayed.
After blood sampling, the patients were given an 800 kcal/d diet for 12 weeks.18 Then blood sampling for plasma adhesin and vWF assays was repeated. Twenty-four-hour urine volumes for urinary albumin excretion were also collected. Anthropometric variables including body weight (light clothes, shoes off), waist-to-hip ratio, and subscapular skinfold thickness were measured. Blood pressure levels were measured at baseline and then each 15 days during caloric restriction by using a standard Riva-Rocci sphygmomanometer and stethoscope. Four sitting blood pressure measurements were taken at 3-minute intervals, and the mean of the latter 3 readings was calculated. Cuffs of appropriate size were used.22
Laboratory Methods
Circulating E-selectin (R&D Systems), ICAM-1 (R&D), and VCAM-1
(R&D) levels were assessed by immunoenzymatic methods. Plasma vWF
levels were also measured by an immunoenzymatic method
(Boehringer Mannheim Co). Plasma insulin levels were assayed by
radioimmunoassay (Ares Serono). Serum total cholesterol,
HDL cholesterol, and triglyceride levels were
assessed by enzymatic methods (Boehringer Mannheim); in
the case of HDL cholesterol, it was measured after
precipitation of LDL and VLDL cholesterol fractions by
phosphotungstate. LDL and VLDL cholesterol levels were
assessed by the Friedewald method.23 Urinary
albumin was evaluated by nephelometry.
Control Groups
Circulating soluble E-selectin, ICAM-1, VCAM-1, and vWF
concentrations were assessed mostly from stored plasma samples from the
already described18 nonobese control subjects (n=16,
52.4±3.5 years) and nonobese hypertensive patients (n=18, 52.3±3.9
years). Procedures and criteria were identical to those used for the
obese groups, but nonobese subjects had a BMI <26
kg/m2.
Statistical Analysis
Statistical significance values among the examined groups were
evaluated by 1-way ANOVA followed by Bonferroni's test and the
Newman-Keuls test for pairwise comparisons. Multiple comparisons were
tested by ANOVA, followed by post hoc analysis for adjusting
the significance levels. Linear regression and correlation were used to
evaluate relationships between variables. Statistical significance
was considered at a value of P<0.05. All data are
presented as mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Data
Obese hypertensives and normotensives had higher fasting insulin levels than did nonobese subjects (the Table). Although normal, urinary albumin excretion values were higher in obese hypertensives than in obese normotensives and controls but not in nonobese hypertensives. This latter group and the obese normotensives showed a higher urinary albumin excretion compared with controls. Urinary albumin was correlated with mean blood pressure levels in obese hypertensives (r=0.572, P=0.005), obese normotensives (r=0.588, P=0.008), nonobese hypertensives (r=0.561, P=0.024), and nonobese normotensives (r=0.490, P=0.039). Serum lipid levels were not significantly different among the groups evaluated (the Table).
|
Obese hypertensives and normotensives had similar levels of circulating VCAM-1, ICAM-1, and E-selectin (Figures 1A, 1B, and 1C, respectively) as well as of vWF (Figure 1D). By contrast, the above variables were significantly higher in the 2 obese subgroups than in their nonobese counterparts (Figure 1). Circulating levels of soluble adhesins and of vWF did not differ between nonobese hypertensives and normotensives (Figure 1).
|
Considered together, obese hypertensives and obese normotensives had plasma concentrations of soluble VCAM-1 that were significantly correlated with plasma LDL levels (Figure 2A), whereas plasma soluble E-selectin levels were directly correlated with BMI (Figure 2B) but not with waist-to-hip ratio or subscapular skinfold thickness. The correlation between plasma E-selectin levels and BMI was also evident in obese hypertensives (P=0.018) and obese normotensive patients (P=0.021) considered separately. A direct correlation was found between plasma vWF levels and BMI in obese hypertensives (r=0.512, P=0.015) and obese normotensives (r=0.477, P=0.039). Plasma vWF levels were not correlated with waist-to-hip ratio or subscapular skinfold thickness. In the nonobese subgroups, neither circulating soluble adhesion molecule nor plasma vWF levels were correlated with any variable.
|
Effects of Weight Loss in Obese Hypertensives
The 12 weeks of caloric restriction reduced BMI (from 33.2±1.7 to
30.6±1.5 kg/m2, P<0.0001),
systolic blood pressure (from 165.6±7.8 to 156.2±6.4
mm Hg, P<0.0001), diastolic blood pressure
(from 105.1±3.5 to 98.3± 6.18 mm Hg, P<0.0001),
urinary albumin (from 16.1±2.2 to 14.8±1.6 µg/min,
P=0.03), fasting plasma insulin (from 125.4±48.3 to
98.4±34.2 pmol/L, P=0.035), and vWF levels (from 1.81±0.26
to 1.58±0.22 KU/L, P=0.003). By contrast, serum total
cholesterol, cholesterol subfractions,
triglyceride, and plasma glucose levels were not
significantly decreased after the same period.
Circulating levels of soluble VCAM-1, ICAM-1, and E-selectin significantly decreased after the diet period (Figures 3A, 3B, and 3C, respectively), the greatest decrement being observed for plasma soluble E-selectin. Changes in plasma VCAM-1, ICAM-1, and E-selectin after weight loss were unrelated to changes in other variables, ie, body weight, blood pressure, fasting insulin, etc. Circulating E-selectin concentrations after weight loss were directly correlated with corresponding values of BMI (Figure 4A).
|
|
Effects of Weight Loss in Obese Normotensives
The 12 weeks of caloric restriction significantly reduced BMI
(from 32.9±1.8 to 31.2±2.1, P=0.02), urinary
albumin (from 14.6±2.3 to 12.2±2.6 µg/min,
P=0.005), fasting plasma insulin (from 118.6±38.3 to
94.4±24.4 pmol/L, P=0.026), and vWF levels (from 1.71±0.18
to 1.48±0.16 KU/L P<0.0001) but not serum
cholesterol, cholesterol subfractions,
triglyceride, or plasma glucose levels.
Circulating soluble VCAM-1, ICAM-1, and E-selectin levels significantly decreased after caloric restriction (Figures 3A, 3B, and 3C, respectively). As in obese hypertensives, plasma soluble E-selectin levels after weight loss were directly correlated with corresponding values of BMI (Figure 4B).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The current report shows increased levels of circulating VCAM-1, ICAM-1, and E-selectin in obese hypertensive and normotensive men. Endothelial activation was unrelated to the presence of hypertension and/or other cardiovascular risk factors. Indeed, plasma soluble adhesion molecule concentrations were elevated in both normotensive and hypertensive obese subjects. Furthermore, obese patients were nondiabetic and nonhyperlipidemic and had no evidence of overt atherosclerosis and/or a parental history of vascular diseases before the age of 60. Moreover, both normotensive and hypertensive obese patients manifested increased levels of the well-known marker of endothelial activation, vWF.16 Although the urinary albumin excretion rate was correlated with blood pressure levels rather than body weight, this marker of endothelial damage24 25 was also higher in obese than in nonobese subgroups. Thus, our data confirm that the endothelium is not activated in uncomplicated hypertension.26 Furthermore, the same data show that obesity per se promotes early endothelial activation, which involves adhesion molecules and the procoagulant agent vWF and which is accompanied by an elevated urinary albumin excretion. Consistent with this, weight loss counteracted such endothelial activation, as indicated by the simultaneous decrements of urinary albumin excretion, plasma vWF, and soluble adhesin levels occurring after 12 weeks of caloric restriction.
As is known, obesity is correlated with an increased risk for developing atherosclerosis.1 2 3 4 In spite of the association of obesity with hypertension, hyperlipidemia, hyperinsulinemia, elevated alcohol consumption, physical inactivity, and cigarette smoking,2 3 4 some evidence supports the concept that obesity per se might increase cardiovascular risk, independent of other risk factors.1
In this regard, the initiating event in atheroma formation is upregulation of endothelial adhesion molecules and the consequent transendothelial migration of circulating leukocytes and monocytes.7 8 Although adhesin expression on the endothelial cell surface cannot be investigated in vivo, the soluble forms of endothelial adhesins have been found in the circulation.11 27 Indeed, a proteolytic process28 leads to the release of soluble VCAM-1,9 ICAM-1,9 10 27 28 and E-selectin9 10 from activated human cultured cells simultaneously with the expression of their membrane-associated forms. Accordingly, significant increments of plasma soluble ICAM-1 levels have been described after a 2-hour angiotensin II infusion,29 ie, the same time course for maximal expression of membrane-associated ICAM-1 by human endothelial cells stimulated with either angiotensin II or various cytokines.9 10 30 31 Therefore, the level of circulating adhesins can be considered a marker of their in vivo expression.11 27
In keeping with this, high plasma adhesin concentrations have been found in atherosclerosis26 30 and in conditions associated with increased cardiovascular risk, ie, type 2 diabetes12 13 and impaired glucose tolerance.15 Whereas ICAM-1 is broadly distributed in tissues,6 VCAM-1 and E-selectin are mainly and exclusively expressed, respectively, by vascular endothelial cells.5 6 Thus, the increased levels of plasma soluble E-selectin and VCAM-1 found in obese patients strongly suggest that the vascular endothelium is activated in human obesity. Again, the elevation of urinary albumin excretion and plasma vWF levels in obese patients and their significant decrements after weight loss further support this hypothesis.
The reasons leading to endothelial adhesin upregulation in human obesity are unclear. A direct relationship between plasma soluble VCAM-1 and LDL levels was found in obese patients. Lysophosphatidylcholine, a component of oxidized LDL, upregulates VCAM-1 expression in human cultured endothelial cells.31 In hyperlipidemic animals, VCAM-1 upregulation is associated with early atherosclerosis.32 Hypercholesterolemia has been associated with increased plasma soluble VCAM-1 concentrations in humans,33 suggesting that circulating LDL may upregulate VCAM-1 in obese subjects due to LDL oxidation. In contrast to this hypothesis, a correlation between circulating LDL and soluble VCAM-1 levels was weak, and our obese patients had normal serum LDL levels. Furthermore, although obese patients manifested increased plasma E-selectin and ICAM-1 concentrations, these latter 2 and the circulating LDL levels were not correlated. Moreover, reduction of circulating LDL levels by 51% was reported to not affect plasma soluble VCAM-1 concentrations in hypercholesterolemic patients.33 Therefore, our data cannot support a role for circulating LDL in favoring VCAM-1 upregulation in obese subjects.
Another possible explanation for our findings could be related to insulin levels and glucose metabolism. Plasma E-selectin34 and ICAM-1 levels35 were elevated in hyperglycemic type 2 diabetics. High glucose levels upregulate E-selectin and ICAM-1 expression in human endothelial cells.36 Thus, changes in plasma glucose levels could upregulate endothelial adhesins in obese people. Against this hypothesis, we studied only euglycemic patients and found no correlations between plasma adhesin and glucose levels. Thus, our data do not support the hypothesis that changes of plasma glucose levels within the normal range might upregulate endothelial adhesion molecules in obese people. Similarly, obese subjects can be significantly insulin resistant and hyperinsulinemic.2 However, plasma insulin and adhesin concentrations were also unrelated in our patients. Thus, further studies are needed to evaluate the possible intriguing relationships among insulin, glucose, and soluble adhesion molecule levels in obese people.
In this regard, our data suggest that obesity per se could overstimulate E-selectin and vWF production. Indeed, we found a significant correlation between circulating E-selectin levels and BMI in both obese hypertensive and obese normotensive groups (Figure 2B). Values of BMI after weight loss were directly correlated with soluble E-selectin levels in both groups (Figures 4A and 4B). Additionally, plasma vWF concentrations were elevated and directly correlated with BMI in obese subjects. In keeping with this, waist-to-hip ratio and subscapular skinfold thickness were unrelated to plasma vWF and E-selectin levels. Unfortunately, no relationship was found between changes in plasma E-selectin and BMI after weight loss. Thus, the role of obesity as a promoter of E-selectin activation needs to be confirmed by further studies.
At variance from our data, 2 elegant reports showed increased plasma soluble E-selectin14 and vWF levels37 in hypertensive patients. However, after exclusion of those with uncontrolled hypertension, vascular damage, severe hypercholesterolemia, and smoking, neither vWF nor E-selectin levels were elevated in hypertensives versus normotensives.14 37 Furthermore, uncontrolled hypertensives were not selected for having ultrasonographically normal arteries and normal glucose tolerance, and approximately two thirds of the study populations were constituted by fertile women.14 37 As a consequence, discrepancies between our data and previous data14 37 simply reflect differences in patient selection.
In conclusion, the current report demonstrates increased levels of plasma soluble E-selectin, ICAM-1, VCAM-1, and vWF and elevated urinary albumin excretion in obese essential hypertensive and normotensive men without atherosclerosis and/or other concomitant risk factors. The pivotal role of obesity as the main promoter of endothelial activation was clearly demonstrated by the marked reductions of soluble adhesin levels observed after weight loss due to caloric restriction. Although normal, circulating glucose and insulin levels were both higher in obese than nonobese groups, suggesting that abnormalities in glucose metabolism might simultaneously induce adipose tissue accumulation and endothelial adhesin upregulation. Whether the observed endothelial activation plays a role in obesity-related atherogenesis remains unsettled and needs further clarification by longitudinal follow-up studies.
Received January 26, 1999; first decision February 22, 1999; accepted May 17, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Stevens J, Cai J, Pamuk ER, Williamson DF, Thun
MJ, Wood JL. The effect of age on the association between body mass
index and mortality. N Engl J Med. 1998;338:1–8.
[Abstract/Free Full Text] - Barret-Connor EL. Obesity, atherosclerosis and coronary artery disease. Ann Intern Med. 1985;103:1010–1019.
- Garrison RJ, Castelli WP. Weight and thirty-year mortality of men in the Framingham study. Ann Intern Med. 1985;103:1006–1009.
- Terry RB, Page WF, Haskell WL. Waist-hip ratio, body mass index and premature cardiovascular disease mortality in US Army veterans during a twenty-three year follow-up study. Int J Obes. 1992;16:417–423.
- Bevilacqua MP, Nelson RM. Selectins. J Clin Invest. 1993;91:379–387.
- Dustin ML, Staunton DE, Springer TA. Supergene families meet the immune system. Immunol Today. 1988;9:213–215.[Medline] [Order article via Infotrieve]
- Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
- Jang Y, Lincoff M, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol. 1994;24:1591–1601.[Abstract]
- Pigott R, Dillon LP, Gearing AJH. Soluble E-selectin, ICAM-1 and VCAM-1 are present in supernatants of cytokine-activated cultured endothelial cells. Biochem Biophys Res Commun. 1992;87:584–589.
- Leeuwenberg JFM, Smeets EF, Neefjes JJ, Shaffer MA, Cinek T, Jeunhomme TMAA, Ahern TJ, Buurman WA. E-selectin and intercellular adhesion molecule-1 are released by activated human endothelial cells in vitro. Immunology. 1993;77:543–549.
- Gearing AJH, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993;14:506–512.[Medline] [Order article via Infotrieve]
- Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann AD. Increased levels of soluble adhesion molecules in type II (non-insulin-dependent) diabetes mellitus are independent of glycaemic control. Thromb Haemost. 1994;72:979–984.[Medline] [Order article via Infotrieve]
- Fasching P, Waldhäusl W, Wagner OF. Elevated circulating adhesion molecules in NIDDM:-potential mediators in diabetic macroangiopathy. Diabetologia. 1996;39:1242–1244.
- Blann AD, Tse W, Maxwell SJR, Waite MA. Increased levels of the soluble adhesion molecule E-selectin in essential hypertension. J Hypertens. 1994;12:925–928.[Medline] [Order article via Infotrieve]
- Ferri C, Desideri G, Baldoncini R, Bellini, De Angelis C, Mazzocchi C, Santucci A. Early activation of vascular endothelium in non-obese, non-diabetic essential hypertensive patients with multiple metabolic abnormalities. Diabetes. 1998;47:660–667.[Abstract]
- Blann AD, McCollum CN. von Willebrand factor, endothelial cell damage and atherosclerosis. Eur J Vasc Surg. 1994;8:10–15.[Medline] [Order article via Infotrieve]
- Blann AD, Bushell D, Davies A, Faragher EB, Miller JP, McCollum CN. von Willebrand factor, the endothelium and obesity. Int J Obes. 1993;17:723–725.
- Ferri C, Bellini C, Desideri G, Di Francesco L, Baldoncini R, Santucci A, De Mattia G. Plasma endothelin-1 levels in obese hypertensive and normotensive men. Diabetes. 1995;44:431–436.[Abstract]
- Licata G, Scaglione R, Avellone G, Ganguzza A, Corrao S, Arnone S, Di Chiara T. Hemostatic function in young subjects with central obesity: relationship with left ventricular function. Metabolism. 1995;44:1418–1422.
- Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction: implication for the syndrome of insulin resistance. J Clin Invest. 1996;97:2601–2610.[Medline] [Order article via Infotrieve]
-
Somigliana E, Vigano P, Gaffuri B, Busacca M, Vignali
M. Human endometrial stromal cells as a source of soluble intercellular
adhesion molecule (ICAM)-1 molecules. Hum Reprod.. 1996;11:1190–1194.
[Abstract/Free Full Text] - Nielsen PE, Jannich H. The accuracy of auscultatory measurement of arm blood pressure in very obese subjects. Acta Med Scand. 1974;195:403–406.[Medline] [Order article via Infotrieve]
- Friedewald WT, Levy RI, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
- Stehouwer CDA, Nauta JJP, Zeldenrust GC, Hackeng WHL, Donker AJM, den Ottolander GJ. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet.. 1993;340:319–323.
- Pedrinelli R, Giampietro O, Carmassi F, Melillo E, Dell'Omo G, Catapano G, Matteucci E, Talarico L, Morale M, De Negri M, Di Bello V. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet. 1994;344:1418.
-
De Caterina R, Basta G, Lazzerini G, Dell'Omo G,
Petrucci R, Morala M, Carmassi F, Pedrinelli R. Soluble vascular cell
adhesion molecule-1 as a biohumoral correlate of
atherosclerosis. Arterioscler Thromb Vasc
Biol. 1997;17:2646–2654.
[Abstract/Free Full Text] - Gearing AJH, Pigott R, Highes J, Rees AJ, Cashman SJ. Soluble forms of vascular adhesion molecules, E-selectin, ICAM-1, and VCAM-1: pathological significance. Ann N Y Acad Sci. 1992;667:324–331.[Medline] [Order article via Infotrieve]
- Budnik A, Grewe M, Gyufko K, Krutman J. Analysis of the production of soluble ICAM-1 molecules by human cells. Exp Hematol. 1996;24:352–359.[Medline] [Order article via Infotrieve]
- Pastore L, Tessitore A, Martinotti S, Ferri C, Desideri G, Bellini C, Alesse E, Gulino A, Santucci A. Angiotensin II promotes ICAM-1 expression in vitro and soluble ICAM-1 secretion in vivo. Circulation. In press.
- Blann AD, McCollum CN. Circulating endothelial cell/leucocyte adhesion molecules in atherosclerosis. Thromb Haemost.. 1994;72:151–154.[Medline] [Order article via Infotrieve]
- Kume N, Cybulsky MI, Gimbrone MA Jr. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leucocyte adhesion molecules in cultured human and rabbit endothelial cells. J Clin Invest. 1992;90:1138–1144.
-
Richardson M, Hadcock SJ, DeReske M, Cybulsky MI.
Increased expression in vivo VCAM-1 and E-selectin by the aortic
endothelium of normolipemic and hyperlipemic diabetic
rabbits. Arterioscler Thromb. 1994;14:760–769.
[Abstract/Free Full Text] -
Hackman A, Abe Y, Insull W, Pownall H, Smith L, Dunn K,
Gotto AM, Ballantyne CM. Levels of soluble cell adhesion molecules in
patients with dyslipidemia. Circulation. 1996;93:1334–1338.
[Abstract/Free Full Text] - Cominacini L, Fratta Pasini A, Garbin U, Davoli A, De Santis A, Campagnola M, Rigoni A, Zenti M, Moghetti P, Lo Cascio V. Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control. Diabetologia. 1995;38:1122–1124.[Medline] [Order article via Infotrieve]
- Ceriello A, Falleti E, Bortolotti N, Motz E, Cavarape A, Russo A, Gonano F, Bartoli E. Increased circulating adhesion molecule-1 levels in type II diabetic patients: the possible role of metabolic and oxidative stress. Metabolism. 1996;45:448–451.
- Baumgartner-Parzer SM, Wagner L, Pettermann M, Gessl A, Waldhäusl W. Modulation by high glucose of adhesion molecule expression in cultured endothelial cells. Diabetologia. 1995;38:1367–1370.[Medline] [Order article via Infotrieve]
- Blann AD, Naqvi T, Waite MA, McCollum CN. Von Willebrand factor and endothelial damage in essential hypertension. J Hum Hypertens. 1993;7:107–111.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J. B Keogh, G. D Brinkworth, M. Noakes, D. P Belobrajdic, J. D Buckley, and P. M Clifton Effects of weight loss from a very-low-carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity Am. J. Clinical Nutrition, March 1, 2008; 87(3): 567 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Song, J. E. Manson, L. Tinker, N. Rifai, N. R. Cook, F. B. Hu, G. S. Hotamisligil, P. M. Ridker, B. L. Rodriguez, K. L. Margolis, et al. Circulating Levels of Endothelial Adhesion Molecules and Risk of Diabetes in an Ethnically Diverse Cohort of Women Diabetes, July 1, 2007; 56(7): 1898 - 1904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Jimenez, R. M. Estepa, R. M. Camacho, R. C. Estrada, F. G. Luna, and F. B. Guitarte Endothelial dysfunction is related to insulin resistance and inflammatory biomarker levels in obese prepubertal children Eur. J. Endocrinol., April 1, 2007; 156(4): 497 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Testa, F. A. Benedetto, B. Spoto, A. Pisano, G. Tripepi, F. Mallamaci, L. S. Malatino, and C. Zoccali The E-selectin gene polymorphism and carotid atherosclerosis in end-stage renal disease Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1921 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Meyer, G. Kundt, M. Steiner, P. Schuff-Werner, and W. Kienast Impaired Flow-Mediated Vasodilation, Carotid Artery Intima-Media Thickening, and Elevated Endothelial Plasma Markers in Obese Children: The Impact of Cardiovascular Risk Factors Pediatrics, May 1, 2006; 117(5): 1560 - 1567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Desideri, M. De Simone, L. Iughetti, T. Rosato, M. L. Iezzi, M. C. Marinucci, V. Cofini, G. Croce, G. Passacquale, S. Necozione, et al. Early Activation of Vascular Endothelial Cells and Platelets in Obese Children J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3145 - 3152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Curat, A. Miranville, C. Sengenes, M. Diehl, C. Tonus, R. Busse, and A. Bouloumie From Blood Monocytes to Adipose Tissue-Resident Macrophages: Induction of Diapedesis by Human Mature Adipocytes Diabetes, May 1, 2004; 53(5): 1285 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Hukshorn, J. H. N. Lindeman, K. H. Toet, W. H. M. Saris, P. H. C. Eilers, M. S. Westerterp-Plantenga, and T. Kooistra Leptin and the Proinflammatory State Associated with Human Obesity J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Lindsberg and A. J. Grau Inflammation and Infections as Risk Factors for Ischemic Stroke Stroke, October 1, 2003; 34(10): 2518 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Mather, H. O. Steinberg, and A. D. Baron Weight Loss and Endothelial Function in Obesity Diabetes Care, June 1, 2003; 26(6): 1927 - 1928. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Desideri and C. Ferri Effects of Obesity and Weight Loss on Soluble CD40L Levels JAMA, April 9, 2003; 289(14): 1781 - 1782. [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Preston, W. Jy, J. J. Jimenez, L. M. Mauro, L. L. Horstman, M. Valle, G. Aime, and Y. S. Ahn Effects of Severe Hypertension on Endothelial and Platelet Microparticles Hypertension, February 1, 2003; 41(2): 211 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Esposito, A. Pontillo, M. Ciotola, C. Di Palo, E. Grella, G. Nicoletti, and D. Giugliano Weight Loss Reduces Interleukin-18 Levels in Obese Women J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3864 - 3866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Bagg, C. Ferri, G. Desideri, G. Gamble, P. Ockelford, and G. D. Braatvedt The Influences of Obesity and Glycemic Control on Endothelial Activation in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5491 - 5497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Targher, R. C. Bonadonna, M. Alberiche, M. B. Zenere, M. Muggeo, and E. Bonora Relation Between Soluble Adhesion Molecules and Insulin Sensitivity in Type 2 Diabetic Individuals: Role of adipose tissue Diabetes Care, November 1, 2001; 24(11): 1961 - 1966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ziccardi, F. Nappo, G. Giugliano, K. Esposito, R. Marfella, M. Cioffi, F. D'Andrea, A. M. Molinari, and D. Giugliano Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functions in Obese Women After Weight Loss Over One Year Circulation, February 19, 2002; 105(7): 804 - 809. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||