Ultrasound may improve patient care

Clinical Rheumatology -     

HSF1 and constitutively active HSF1 improve vascular endothelial function (heat shock proteins improve vascular endothelial function)

We have been examining the role of heat shock factor 1 (HSF1) in the pleiotropic effects of statins. In parallel studies, we found that statin induces the nuclear translocation of HSF1 and that a decoy oligonucleotide encoding the heat shock element inhibits the statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase (eNOS) and thrombomodulin. Also, in vascular endothelial cells, increases in the expression of human HSF1 corresponded with elevated steady-state levels of eNOS and thrombomodulin and reduced levels of endothelin-1 and plasminogen activator inhibitor-1. We also found that heat shock proteins induced eNOS and thrombomodulin expression and reduced PAI-1 and ET-1 expression. In particular, a combination of HSP70 and HSP90 strongly induced eNOS expression and reduced PAI-1 expression. In the current studies, we generated a constitutively active form of HSF1 and found that it is more effective than the wild-type HSF at inducing thrombomodulin and eNOS expression and decreasing endothelin-1 and plasminogen activator inhibitor-1 expression. These results show that the wild-type and constitutively active forms of HSF1 induce anticoagulation and relaxation factors in vascular endothelial cells and could therefore be used to treat cardiovascular disease.     

Oral contraceptives improve endothelial function in amenorrheic athletes

Athletic amenorrhea has been associated with endothelial dysfunction and unfavorable lipid profile. Estrogen substitution may reverse these metabolic consequences. The aim of this study was to evaluate the effects of oral contraceptives (OCs) on endothelial function measured as flow-mediated dilatation (FMD) of the brachial artery, the lipid profile, and blood markers of endothelial activation (inflammation) in amenorrheic athletes. Age- and body mass index-matched groups of young endurance athletes with amenorrhea (n = 11), regularly cycling athletes (n = 13), and sedentary controls (n = 12) were examined before and after 9 months of treatment with a low dose, monophasic, combined OC (30 mug ethinyl estradiol and 150 mug levonorgestrel). The amenorrheic athletes displayed the lowest FMD at baseline and the largest increase after OC treatment. FMD also increased in the control group, but not in the regularly menstruating athletes, who had the highest values of FMD before treatment. All three groups, particularly the controls, showed moderate unfavorable changes in the lipid profile in accordance with previous known effects of a second generation OC. Furthermore, there was an overall increase in some inflammatory markers (high sensitive C-reactive protein and TNF-alpha) and a decrease in one of the markers (vascular cell adhesion molecule-1). We conclude that amenorrheic athletes benefit from treatment with OC with respect to endothelial function. OC treatment is also associated with some modest alterations in the lipid profile and in markers of inflammation.     

Experimental approach to improve endothelial barrier function in myocardium

Recently, we showed that activated factor XIII (FXIIIa) has a direct influence on permeability (P) of cultured endothelial monolayer. Clinical investigation on children operated on for congenital heart disease has demonstrated a distinct correlation between decrease of endothelial barrier function (edema formation) and reduced FXIII activity. Our experiments investigated whether significant effects of FXIII could also be shown in a full-organ model. The effect of FXIII on endothelial barrier function was studied by determining the passage of trypan blue-labeled albumin in a model of cultured monolayers of porcine aortic endothelial cells and changes in myocardial water content of saline-perfused rat hearts in a Langendorff-circuit. The plasma FXIIIa (1 U/ml) reduced albumin permeability of aortic endothelial monolayers within 20 minutes from a basal value of 5.9±0.4×10^–6 cm/second by 30±7% whereas the nonactivated plasma FXIII had no effect on permeability. Reduction of permeability to the same extent (by 34±9%) could also be obtained with a thrombin-activated recombinant factor XIII A subunit (rhu FXIII; 1 U/ml) in this culture model. The effect of factor XIII A* on permeability was dose dependent with maximum effect at 5 U/ml (52±11% reduction of permeability compared with control), and existed even if cells had hyperpermeability stress (KCN/2-DG). Activated rhuFXIII prevented the increase in myocardial water content in anoxic-reperfused rat hearts (448±24 vs 517±29 ml/100g dry weight). The data of the present study show that FXIII has a stabilizing effect at the site of endothelial cells not only in cultured monolayers but also in a model of the anoxic perfused rat heart.Presented in part at the 40th Annual World Congress, International College of Angiology, Lisbon, Portugal, June 1998.     

改善高血压患者血管内皮功能的药物治疗进展

高血压病是严重威胁人类健康和生命的常见疾病。有研究证实人类的高血压患者存在血管内皮功能减退,后者又加速了高血压靶器官的损害。目前认为血管内皮细胞所分泌的一氧化氮(NO)/内皮素(ET-1)的失衡在高血压的发生、发展中起重要作用。内皮细胞是"内皮-高血压-心血管事件"链的始动因子和载体[1]。     

Hormone replacement therapy may improve hepatic function in women with Turner's syndrome

OBJECTIVE: Women with Turner's syndrome (TS) have recently been shown to be at an increased risk of developing chronic liver disease. There has been some concern that oestrogen replacement therapy may exacerbate hepatic dysfunction. The aim of this study was to assess hepatic function in women with TS and to determine the effect of oral oestradiol valerate on liver enzymes. DESIGN AND PATIENTS: A retrospective review of liver enzymes of 80 women with TS, followed by a prospective study looking at serum liver enzyme concentrations in 20 women with TS following 3 months on and off hormone replacement therapy (HRT) (oestradiol valerate, 2 mg/levonorgestril 75 microg). MEASUREMENTS: Liver enzymes (gamma glutamyl transferase, aspartate transaminase and alkaline phosphatase), albumin and bilirubin were measured on and off HRT. Viral hepatitis serology and liver autoantibodies were tested in patients with abnormal liver function. RESULTS: Thirty-five out of 80 women (44%) had elevated serum liver enzyme concentrations. Two women (2.5%) had a mildly raised serum bilirubin, but protein synthesis was normal in all subjects. HRT resulted in a significant fall in all liver enzymes (P < 0.05) but did not affect serum protein concentrations CONCLUSIONS: Women with Turner's syndrome often have elevated liver enzymes. Oestrogen/progestagen therapy using oestradiol valerate improves liver function in this group of patients. The mechanisms behind this are unclear.     

Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men.

BACKGROUND: The regulatory function of the endothelium is altered in hypercholesterolemia, and the subsequent endothelial dysfunction plays a central role in the development of atherosclerosis. OBJECTIVE: To determine whether endothelial function in hypercholesterolemic patients is affected by replacing a saturated fat-enriched diet with a low-fat, low-saturated fat diet (the U.S. National Cholesterol Education Program stage 1 [NCEP-1] diet) or a diet rich in monounsaturated fat (such as that common in Mediterranean countries). DESIGN: Intervention dietary study with a baseline phase and two randomized crossover dietary periods. SETTING: Hospital Universitario Reina Sofía, Córdoba, Spain. PATIENTS: 22 hypercholesterolemic men. INTERVENTION: Patients followed a diet high in saturated fat, then were assigned in a crossover design to the NCEP-1 diet or a Mediterranean diet. Each dietary period lasted 28 days. MEASUREMENTS: Plasma P-selectin levels, lipid concentrations, and endothelial function. RESULTS: Compared with the saturated fat diet, flow-mediated dilatation increased during the Mediterranean diet but not during the NCEP-1 diet. In addition, levels of plasma cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and P-selectin decreased during the NCEP-1 and Mediterranean diets. CONCLUSION: In hypercholesterolemic men, diets low in fat (especially saturated fat) and diets rich in monounsaturated fats improve endothelial function.     

Good continuity of care may improve quality of life in Type 2 diabetes

Some features of diabetes care and diabetes treatment regimen which may have an impact on health-related quality of life (HRQOL) in people with diabetes were studied cross-sectionally using the SF-20 questionnaire. Of the 381 subjects with Type 2 diabetes aged under 65 years, 260 (68%) participated in the study. On univariate analysis, HRQOL was associated with regular clinical review (check-up at least twice a year) and continuity of care (the same GP for at least 2 years), education by a diabetes nurse, and satisfaction with diabetes education. No associations were found between the HRQOL dimensions and home glucose monitoring, participation in educational courses, or satisfaction with care. On logistic regression analysis only good continuity of care was significantly associated with the better well-being dimensions of the SF 20 (ORs 2.5-6.0). However, good continuity of care was also associated with less satisfactory glucose control (HbA(1c) 8.9 +/- 2.0 (+/- SD) vs 8.3 +/- 2.0%, P=0.04). It is concluded that a permanent physician-patient relationship may improve HRQOL in subjects with Type 2 diabetes, but further prospective studies are needed to confirm this finding.     

Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats

Red wine polyphenols (RWPs) have been reported to prevent hypertension and endothelial dysfunction. Several individual RWPs exert estrogenic effects. We analyzed the possible in vivo protective effects on blood pressure and endothelial function of RWPs in female spontaneously hypertensive rats (SHR) and its relationship with ovarian function. RWPs (40 mg/kg by gavage) were orally administered for 5 weeks. Ovariectomized rats showed both increased isoprostaglandin F(2alpha) excretion and aortic superoxide production and reduced relaxant response to acetylcholine and contraction to the endothelial nitric oxide synthase (eNOS) inhibitor l-NAME measured in the aorta but similar blood pressure, as compared with sham-operated rats. Moreover, in ovariectomized rats aortic eNOS expression was unchanged, whereas caveolin-1, angiotensin II receptor (AT)-1, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was increased compared with sham-operated rats. In both ovariectomized and sham-operated SHR, RWPs reduced systolic blood pressure, urinary isoprostaglandin F(2alpha) excretion, and aortic O(2)(-) production, improving the endothelium-dependent relaxant response to acetylcholine in SHR. These changes were associated with unchanged aortic eNOS expression, whereas caveolin-1 was increased and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was reduced. RWPs had no effect on the AT-1 overexpression found in ovariectomized animals. All these results suggest that a chronic treatment with RWPs reduces hypertension and vascular dysfunction through reduction in vascular oxidative stress in female SHR in a manner independent of the ovarian function.     

Lowering serum urate does not improve endothelial function in patients with type 2 diabetes

Aims/hypothesis Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group. Methods Intravenous urate oxidase (1.5 mg) was administered to ten patients with type 2 diabetes and ten healthy participants in a two-way, randomised, placebo-controlled, crossover study. Forearm blood flow responses to intra-brachial acetylcholine, sodium nitroprusside and N ^G-monomethyl-l-arginine (L-NMMA) were measured using venous occlusion plethysmography. The augmentation index (AIx) was determined by pulse wave analysis as a measure of large arterial stiffness. Results Acetylcholine and L-NMMA evoked lesser responses in patients with type 2 diabetes than in healthy participants. Baseline AIx was higher in patients with type 2 diabetes (mean ± SD: 13.1 ± 6.9%) than in healthy participants (2.0 ± 5.1%; p = 0.006). Urate oxidase lowered serum uric acid concentrations by 64 ± 11% (p < 0.001), but this had no effect on forearm blood flow responses or AIx in either group. Conclusions/interpretation Substantial short-term lowering of uric acid did not have a direct vascular effect, suggesting that, on its own, this might not be an effective strategy for restoring endothelial function in patients with type 2 diabetes.     

Circulating microparticles released during dyslipidemia may exert deleterious effects on blood vessels and endothelial function

AimsTo compare the bioactivity of circulating microparticles (MPs) isolated from dyslipidemic Psammomys obesus (P. obesus) fed a high-energy diet (HED) with those released from healthy P. obesus fed a normal diet (ND).MethodsVascular reactivity of aortic rings was evaluated by myography, after 24 h incubation in the absence or in the presence of circulating MPs isolated, by differential centrifugations, from the plasma of animals subjected to HED (MPs_HED) or ND (MPs_ND) for 12 weeks. Human umbilical vein endothelial cells (HUVECs) were treated for 24 h with MPs_HED or MPs_ND animals and subjected to immunofluorescence staining of caveolin-1 (cav-1), intercellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase (eNOS), F-actin and reactive oxygen species (ROS) detection.ResultsThe HED exerted a distinctly pronounced hyperlipidemic effect marked by plasmatic increase of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride (TG). Both MPs_ND and MPs_HED induced a significant reduction of maximal relaxation induced by acetylcholine (ACh). Interestingly, MPs_HED significantly decreased eNOS expression up to ~25% and increased ROS production up to ~75% on in vitro treated HUVECs. Moreover, in HUVECs, MPs_HED significantly decreased cav-1 expression up to ~50% whereas significant increase of ICAM-1 expression by about 2-fold approximately was observed.ConclusionOur experimental study demonstrated the dual role of MPs on vascular function by modulating endothelial cell function. Furthermore, MPs may be considered as vectors of a bioactive information contributing to inflammation and vascular damage.     

Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.