The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic review.

OBJECTIVE: The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance. DESIGN: The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). RESULTS: A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study. CONCLUSIONS: Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

A single meal has the potential to alter brain oxylipin content.

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.

Probiotic administration in congenital heart disease: a pilot study.

OBJECTIVE: To investigate the impact of probiotic Bifidobacterium longum ssp. infantis on the fecal microbiota and plasma cytokines in neonates with congenital heart disease. STUDY DESIGN: Sixteen infants with congenital heart disease were randomly assigned to receive either B. infantis (4.2 × 10(9) colony-forming units two times daily) or placebo for 8 weeks. Stool specimens from enrolled infants and from six term infants without heart disease were analyzed for microbial composition. Plasma cytokines were analyzed weekly in the infants with heart disease. RESULTS: Healthy control infants had increased total bacteria, total Bacteroidetes and total bifidobacteria compared to the infants with heart disease, but there were no significant differences between the placebo and probiotic groups. Plasma interleukin (IL)10, interferon (IFN)γ and IL1ß levels were transiently higher in the probiotic group. CONCLUSION: Congenital heart disease in infants is associated with dysbiosis. Probiotic B. infantis did not significantly alter the fecal microbiota. Alterations in plasma cytokines were found to be inconsistent.

Under-filled blood collection tubes containing K2EDTA as anticoagulant are acceptable for automated complete blood counts, white blood cell differential, and reticulocyte count.

Current laboratory standards from Clinical Laboratory Standards Institute (CLSI) and manufacturer's (Becton Dickinson) data indicate that under-filling K(2)EDTA blood collection tubes can result in erroneous hematology values. To accommodate under-filled tubes and reduce collection volumes while optimizing our automation, we explored the acceptable limit of under-filled tubes for hematology values. We collected 8.0 ml of blood from 30 normal adult volunteers. Each donation was aliquoted in the following volumes: 4.0, 2.0, 1.0, 0.5 ml x 2. These samples were analyzed within 1 h of blood collection on Sysmex XE-2100 (Sysmex America Inc., Mundelein, IL, USA) for complete blood count, reticulocyte, and white blood cell differentials. Results of the under-filled tubes were compared to those of the standard volume. The Deming regression analysis show excellent correlation for all parameters between each under-filled blood collection volume compared to a standard 4 ml volume. The Bland and Altman analysis shows good agreement between both 1.0 and 2.0 ml compared to a 4.0 ml volume. The 0.5 ml compared to a 4.0 ml volume, however, shows increased variation on many parameters. In addition all three collection volumes show negative bias compared to the standard volume for platelet count, but the difference is considered insignificant with a percent difference of 5.5%, 3.2%, and 1.5% for 0.5, 1.0, and 2.0 ml collection volume respectively. Finally for 0.5 ml collection volume we noticed a low level of false positive flagging rate for white blood cell. Acceptable complete blood count values of under-filled powdered K(2)EDTA tubes can be obtained with as little as 1.0 ml of blood.

Multinutrient supplement containing ephedra and caffeine causes weight loss and improves metabolic risk factors in obese women: a randomized controlled trial.

OBJECTIVE: To determine the safety and efficacy of a dietary supplement with a low dose of ephedra and caffeine in overweight/obese premenopausal female subjects. DESIGN: A 9-month, double-blind, randomized control study compared the efficacy and safety of a dietary supplement with ephedra and caffeine to a control supplement. SUBJECTS: Sixty-one healthy, premenopausal women with body mass index (BMI) from 27 to 39 kg/m2 were randomly assigned and received a dietary supplement (40 mg/day ephedra alkaloids, 100 mg/day caffeine, high potency mixture of vitamins, minerals, omega-3 fatty acids) or a control supplement for 9 months. EFFICACY: changes in body weight, body composition, lipids, insulin, leptin, adiponectin, ghrelin, and self-reports of physical activity, diet and quality of life indices. SAFETY: blood pressure, heart rate, electrocardiograms, urinalysis, blood histology, serum chemistry measures and self-reported symptoms. RESULTS: Forty-one women completed the study. The treatment group lost significantly more body weight (-7.18 kg) and body fat (-5.33 kg) than the control group (-2.25 and -0.99 kg, respectively), and showed significant declines in heart rate, serum cholesterol, triglycerides, cholesterol to high-density lipoprotein ratio, glucose, fasting insulin, and leptin. Blood pressure, electrocardiograms, other clinical chemistry measures, blood histology, urinalysis, and self-reported physical activity were similar in the groups. Minor symptoms included dry mouth, insomnia, nervousness and palpitations. The treatment group reported more energy and decreased appetite compared to controls and scored higher on a quality of life domain assessing vitality. CONCLUSION: A dietary supplement containing a low potency ephedra/caffeine mixture appeared safe and effective in causing loss of weight and body fat, and improving several metabolic parameters, including insulin sensitivity and lipid profiles when tested under physician supervision. Such supplements could be a useful tool to assist with weight loss.

Raman spectroscopic analysis of biochemical changes in individual triglyceride-rich lipoproteins in the pre- and postprandial state.

Individual triglyceride-rich lipoprotein (TGRL) particles derived from human volunteers are nondestructively analyzed by laser tweezers Raman microspectroscopy, and information on their composition and distribution is obtained. The Raman signature of single optically trapped very low-density lipoproteins (VLDL), a subclass of TGRL, which play an important role in cardiovascular disease, exhibits distinct peaks associated with molecular vibrations of fatty acids, proteins, lipids, and structural rearrangements of lipids. Our analysis of pre- and postprandial VLDL exhibits the signature of biochemical changes in individual lipoprotein particles following the consumption of meals. Interaction of VLDL with endothelium leads to the breakdown of complex triacylglycerols and the formation of a highly ordered core of free saturated fatty acids in the particle. A particle distribution analysis reveals trends in the degree to which this process has occurred in particles at different times during the postprandial period. Differences in particle distributions based on the different ratios of polyunsaturated to saturated fats in the consumed meals are also easily discerned. Individual lipoprotein particles hydrolyzed in vitro through addition of lipoprotein lipase (LpL) exhibit strikingly similar changes in their Raman spectra. These results demonstrate the feasibility of monitoring the dynamics of lipid metabolism of individual TGRL particles as they interact with LpL in the endothelial cell wall using Raman spectroscopy.

Exponential processes in human auditory excitation and adaptation.

Peripheral auditory adaptation has been studied extensively in animal models, and multiple exponential components have been identified. This study explores the feasibility of estimating these component processes for human listeners with a peripheral model of adaptation. The processes were estimated from off-frequency masked detection data that probed temporal masking responses to a gated narrowband masker. The resulting response patterns reflected step-like onset and offset features with characteristically little evidence of confounding backward and forward masking. The model was implemented with linear combinations of exponential functions to represent the unadapted excitation response to gating the masker on and then off and the opposing effects of adaptation in each instance. The onset and offset of the temporal masking response were assumed to be approximately inverse operations and were modeled independently in this scheme. The unadapted excitation response at masker onset and the reversed excitation response at masker offset were each represented in the model by a single exponential function. The adaptation processes were modeled by three independent exponential functions, which were reversed at masker offset. Each adaptation component was subtractive and partially negated the unadapted excitation response to the dynamic masker. This scheme allowed for quantification of the response amplitude, action latency, and time constant for the unadapted excitation component and for each adaptation component. The results reveal that (1) the amplitudes of the unadapted excitation and reversed excitation components grow nonlinearly with masker level and mirror the 'compressive' input-output velocity response of the basilar membrane; (2) the time constants for the unadapted excitation and reversed excitation components are related inversely to masker intensity, which is compatible with neural synchrony increasing at masker onset (or offset) with increasing masker strength; (3) the composite strength of adaptation levels off at high masker levels; this 'saturation' response is consistent with a diminished contribution from peripheral neural adaptation processes at high sound levels; and (4) the response dynamics for two of the adaptation components correspond generally to those for the 'very rapid'/'rapid' processes and 'short-term' processes described in animal studies of peripheral neural adaptation. The action latency of a third adaptation component suggests the role of a second-order peripheral or central process. This modeling exercise (1) indicates that multiple adaptation processes, whatever their origins, contribute substantively to the form of the temporal masking response and (2) supports a sum-of-exponentials scheme for estimating properties of the component processes.

Chronic estradiol treatment attenuates stiffening, glycoxidation, and permeability in rat carotid arteries.

Aging-related changes in vascular stiffening and permeability are associated with cardiovascular disease. We examined the interaction of estradiol on the aging process in vascular tissue from rats by assessing the changes in endothelial layer permeability, arterial compliance, and glycoxidative damage levels. We isolated carotid arteries from ovariectomized (OVX) rats that underwent 1 yr of estrogen treatment with subcutaneous pellets and a subsequent 1 mo of cessation of treatment. Endothelial layer permeability and arterial compliance were determined using quantitative fluorescence microscopy. Endothelial layer permeability was reduced with estradiol treatment (estrogen groups, 2.58 +/- 0.21 ng dextran x min(-1) x cm(-2) vs. nonestrogen groups, 4.01 +/- 0.30 ng dextran x min(-1) x cm(-2); P < 0.05). Additionally, arteries from animals treated with estradiol had an increased compliance index (estrogen groups, 82.9 +/- 3.8 mm2. Torr vs. nonestrogen groups, 69.3 +/- 3.2 mm2. Torr; P < 0.05). Estradiol treatment also reduced levels of pentosidine, which is a specific marker of glycoxidative damage (estrogen groups, 0.11 +/- 0.03 pmol pentosidine/nmol collagen vs. nonestrogen groups, 0.20 +/- 0.03 pmol pentosidine/nmol collagen; P < 0.05). These results indicate that estradiol has multiple chronic vasculoprotective effects on the artery wall to maintain normal vascular wall function.

Predictors of plasma triglyceride elevation in patients participating in a coronary atherosclerosis treatment program.

PURPOSE: Low-fat, high-carbohydrate diets have been used successfully to prevent and treat coronary heart disease, although these diets have been shown to cause elevations in fasting plasma triglyceride concentrations. The present study investigated metabolic factors (glucose, insulin, body weight) associated with changes in plasma triglyceride concentrations in patients participating in a comprehensive, multidisciplinary program, which included the use of a very low-fat diet designed to regress atherosclerotic cardiovascular disease. METHODS: Thirty-six patients were entered into the study and placed on a 10% fat diet. Body mass index and fasting plasma insulin, glucose, lipids, and apolipoproteins were assessed at entrance into and after 3 months of participation in the program. Statistical analysis (discriminant function analysis) was used to identify factors that predicted elevations in plasma triglyceride that occurred during therapy. RESULTS: For the entire group, significant reductions in body weight (-2.4%), fasting glucose (-6%), total cholesterol (-8%), and low-density lipoprotein cholesterol (-11%) were observed, while insulin and triglycerides showed no significant changes. Twenty-one of the patients experienced an increase in fasting triglyceride concentration of 10% or greater. CONCLUSIONS: Three variables (baseline body mass index and fasting triglyceride and insulin concentrations) accurately classified 90% of those who would experience a > or = 10% elevation in triglycerides (P = 0.0002) and 67% of those who experienced no change. The present analysis provides a practical algorithm for clinicians to predict which patients will experience significant elevations in plasma triglyceride concentration when undergoing risk factor reduction that includes the consumption of a very low-fat, high-carbohydrate diet.

Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants.

Focal small bowel perforation (FSBP) occurs most commonly in the ileum of extremely low-birth-weight (ELBW) infants. Early postnatal dexamethasone (EPD) administration results in an increased risk for FSBP in this patient population, but the mechanism by which this occurs is unknown. Infants with FSBP have healthy mucosa but thinned smooth muscle, suggesting a mechanism involving the muscularis propria for these perforations. One explanation for these findings would be that dexamethasone alters the tissue availability of pertinent growth factors to the smooth muscle. To explore this possibility, we administered dexamethasone or saline by intraperitoneal injection to newborn mice for 3 days (dosed at 1 microg/g of body weight/day) to simulate EPD protocols. The animals were sacrificed after 72 h of treatment and their ileums harvested and prepared for microscopy. Immunolocalization was performed for three related growth factors (epidermal growth factor [EGF], heparin-binding EGF [h-EGF], and transforming growth factor alpha [TGF-alpha]) and their common receptor. We found TGF-alpha to be abundant and discretely localized in the muscularis propria in control animals but to be diminished in dexamethasone-treated animals. EGF-receptor immunostaining was also decreased with dexamethasone but there was minimal to no detection of EGF or h-EGF in either treatment condition. Surgical and autopsy specimens of the ileum were obtained from seven ELBW infants who either received EPD or not. These tissues were used for immunolocalization of the same growth factors and similar distributions for TGF-alpha were observed in several of these cases. These findings are consistent with an autocrine role for TGF-alpha in ileal smooth muscle proliferation and suggest a mechanism by which EPD might mediate smooth muscle thinning.

Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group.

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

Direct visualization of lipid deposition and reverse lipid transport in a perfused artery : roles of VLDL and HDL.

The major goal of this study was to determine the interactions of VLDL surface and core lipids with the artery wall. We first demonstrated in vitro that surface lipid in VLDL could be traced using the phospholipid-like fluorescent probe 1,1'-dioctadecyl-3,3, 3',3'-tetramethyl-indocarbocyanine (DiI). The core of VLDL particles was traced by fluorescently labeling apolipoprotein B with TRITC. The labeled VLDLs were perfused through rat carotid arteries, and accumulation of the fluorescently labeled VLDL components in the arterial walls was determined by quantitative fluorescence microscopy. Addition of lipoprotein lipase increased the accumulation of both DiI and TRITC by >2.3-fold. Histological examination showed that DiI and TRITC were primarily localized to the endothelial layer; however, DiI also accumulated as small "lakes" deeper in the artery, in a subendothelial position. Addition of HDL to the perfusion decreased the accumulation of surface lipid and apolipoprotein B-containing particles and eliminated the DiI lakes. Moreover, the increase in endothelial layer permeability associated with lipolysis was attenuated 21% by HDL. If VLDL surface lipid first was allowed to accumulate in the arterial wall, its subsequent rate of loss was more than twice as fast if HDL was included in the perfusate. These studies directly demonstrate atherogenic effects of VLDL lipolysis and their inhibition by HDL.

Smoking and cardiovascular disease.

Mainstream and ETS exposure are strong risk factors for cardiovascular disease in men and women. The relationships between smoking and cardiovascular disease result from multiple mechanisms that interact to contribute to atherosclerosis, vascular injury, thrombosis, and vascular dysfunction. We are only now beginning to understand how smoking contributes to the genesis and progression of cardiovascular disease. Because of the complexity of the interactions between nicotine and the components of MSS, ETS, and sidestream smoke with the vasculature, it will take a great deal of time and effort to fully unravel the mechanisms by which smoking contributes to cardiovascular disease. In addition, cardiovascular risk in female smokers is complicated by hormonal variables that may contribute to greater relative risk. It is important that health care providers, educators, and policy makers recognize the changing patterns of smoking and the impact of smoking on cardiovascular disease, and continue campaigns aimed at enhancing smoking cessation in the general population and in teens. Rigorous research is needed on the changing cultural, psychosocial, and environmental factors that influence tobacco use to improve our understanding of racial/ethnic smoking patterns, and identify strategic tobacco control opportunities. The capacity of tobacco control efforts to keep pace with patterns of tobacco use and cessation depends on timely recognition of emerging prevalence and cessation patterns and the resulting development of appropriate community-based programs to address the factors involved. Smoking trends today will determine how heavy the health burden of cardiovascular disease and others will be among communities tomorrow. Programs that aim at early intervention and reflect cultural diversity will be the cornerstone in the battle against tobacco use. Continued interest in research, educational, and prevention efforts are needed to help curb the risk of cardiovascular disease from smoking in men and women.

17beta-estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation.

Estrogen replacement therapy has been shown to attenuate atherogenesis, although the mechanisms for this effect are incompletely defined. Previously, we showed that 17-beta estradiol (estradiol) attenuated oxidant stress-induced increases in vascular low density lipoprotein (LDL) accumulation. It was unclear whether estradiol's effect was imparted on the lipoprotein particle or the artery wall. To examine this, we chronically treated rats with the following sex hormones: low estradiol, high estradiol, progesterone, low estradiol + progesterone, placebo, or control. Carotid arteries (n = 8/group) were isolated and perfused with fluorescently labeled LDL. Rates of LDL accumulation were measured before and after treatment with 10 ng/ml tumor necrosis factor-alpha (TNF) using quantitative fluorescence microscopy. We observed a 50% decrease in basal LDL accumulation rates (P < 0.01) and a 25% decrease in endothelial layer permeability (P < 0.01) in arteries from estradiol-treated animals. There was no effect of hormone replacement on rate of TNF-induced LDL accumulation (P = 0.451), while incubation of LDL with 65 pg/ml estradiol attenuated the TNF effect (P < 0.01). These experiments suggest two independent mechanisms of anti-atherogenic protection by estradiol: 1) decreased endothelial layer permeability; and 2) incorporation of estradiol into the LDL particle and prevention of LDL binding to the artery wall.

The clinical impact of increased sensitivity PT and APTT coagulation assays.

To determine how more-sensitive prothrombin time (PT) and activated partial thromboplastin time (aPTT) reagents affected the number and distribution of abnormal test results and whether the increased sensitivity for deficiencies resulted in improved diagnosis of clinically significant coagulopathies, we retrospectively compared preoperative coagulation screening data for 140 children undergoing open heart surgery after the reagent change with a similar group of 135 before the change. The more sensitive reagents resulted in a higher rate of abnormal values, but no increase in the identification of clinically significant hemostatic abnormalities. Of 67 patients with abnormal aPTTs in the group screened with more sensitive reagents, 63 had no further workup. No patients in either group were diagnosed subsequently with a coagulopathy because of unexpected bleeding. An abnormal test result did not predict the need for perioperative blood products. We hypothesize that the high frequency of abnormal aPTTs led to physician "desensitization" about the merit of coagulation screening. Therefore, we question the usefulness of preoperative coagulation screening of the pediatric cardiac surgery patient, particularly since lasting changes in physician perception regarding the clinical significance of abnormal values may lead to missed diagnoses in other settings.

Lifestyle modification program in management of patients with coronary artery disease: the clinical experience in a tertiary care hospital.

OBJECTIVES: The authors examined clinical outcomes in 71 male and female patients with coronary atherosclerosis who enrolled in a 2-year, independent-living, lifestyle modification program. The findings in 43 patients who completed the program were compared with those in 28 patients who dropped out of the program. BACKGROUND: Clinical studies suggest that lifestyle modification of risk factors for coronary atherosclerosis reduces subsequent cardiac events but there are very few reports of the effect of these programs in patients living independently. METHODS: Patients with diagnosed coronary atherosclerosis were managed for a 2-year period in a structured multidisciplinary program by a team that included two cardiologists, a nurse, a dietitian, an exercise physiologist, and a clinical psychologist. The overall aim of the program was to normalize or control all major reversible cardiovascular risk factors. Patients were required to participate in several weekly sessions for exercise, meditation/stress reduction training, dietary education and counseling, and participatory dinners. There was a strong emphasis on patient's self care, inclusion of support members, and regular monitoring of and feedback to patients. RESULTS: Data comparing baseline and 2-year outcomes showed a significant reduction in body weight, dietary intake of total/saturated fat and cholesterol, serum low- and high-density lipoprotein concentration, and an increase in exercise capacity. In the compliant group, the incidence of cardiac events was 2.3% over 2 years. CONCLUSION: Multidisciplinary lifestyle modification programs addressing cardiovascular risk factors are known to have a significant impact upon cardiac risk factors in patients with coronary atherosclerosis. Data show that these changes can be accomplished in independent-living patients in a program offered through a routine cardiology service. However, compliance is an important issue in these self-regulated programs.

17 beta-estradiol reduces glycoxidative damage in the artery wall.

Glycoxidative damage in the vasculature has been linked to atherosclerotic cardiovascular disease. Estrogens protect against the development and progression of atherosclerosis. Because estrogens are potent antioxidants that also effect glucose metabolism, part of their protection against atherosclerosis could be through attenuation of glycoxidative damage in the vascular wall. In this study, we tested the hypothesis that chronic estradiol administration is associated with decreased levels of glycoxidative damage in arterial walls. We harvested and examined iliac arteries from ovariectomized, 8-month-old rats that had been implanted for 6 months with 1 of the following subcutaneous hormone pellets: low estradiol (2.5 mg estradiol), high estradiol (25 mg estradiol), P4 (200 mg progesterone), low estradiol and P4, placebo (no hormone), or control (no implant). Using pentosidine as a biomarker of glycoxidative damage, we found that all vessels from rats receiving estradiol (low estradiol, high estradiol, and low estradiol+P4) exhibited a 50% reduction in glycoxidative damage compared with P4, placebo, and control vessels (P<0.05). Consistent with this finding, we observed that estradiol-treated rats had a 30% decrease in tissue levels of hydroperoxides, a marker of oxidative stress. Finally, estradiol-treated rats had a small, but significant, decrease in plasma glucose levels (P<0.01). In summary, we report the novel finding that chronic estrogen administration is associated with significant decreases in glycoxidative damage and oxidative stress in the arterial wall. It seems likely that these actions may constitute a mechanism by which estrogen attenuates the progression of atherosclerosis.

Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 beta-estradiol.

-Current research suggests that estrogen may have primary effects on the artery wall. To investigate the mechanisms of female sex hormone actions in the artery wall, we used an isolated, perfused, rat carotid artery model to examine the effects of estradiol on the rates of accumulation of normal (N-LDL) and minimally modified (MM-LDL) low density lipoprotein in ovariectomized rats. N-LDL, MM-LDL, and oxidized LDL (OX-LDL) were fluorescently labeled and perfused into individual arteries. The rate of LDL accumulation was measured by quantitative fluorescence microscopy before and after treatment with estradiol (1 nmol/L, 272 pg/mL). Estradiol had no effect on the rate of N-LDL accumulation (45+/-12 versus 48+/-15 ng cholesterol per cm2 per h). However, estradiol significantly decreased the rate of MM-LDL (240+/-48 versus 160+/-48 ng cholesterol per cm2 per h; P<0.05) and OX-LDL (191+/-53 versus 112+/-36 ng cholesterol per cm2 per h; P<0.05) accumulation. Further experiments showed that perfusion of unlabeled MM-LDL (100 microgram/mL) increased endothelial layer permeability when the rate of accumulation of a water-soluble, fluorescently labeled, reference molecule (64 000-molecular weight dextran) was determined before and after perfusion of MM-LDL (319+/-96 versus 510+/-191 ng per cm2 per h, n=6 arteries; P<0.05). Estradiol prevented the expected increase in the rate of dextran accumulation when perfused with MM-LDL (control, 415+/-49 ng per cm2 per h and MM-LDL+estradiol, 415+/-160 ng per cm2 per h). Our studies show that estradiol prevents compromise of the endothelial barrier mediated by MM-LDL and attenuates accumulation of MM-LDL in the artery wall.

17beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall.

Estrogens have direct effects on the vascular wall that may prevent the development of atherosclerosis. In particular, estrogens, such as 17beta-estradiol (estradiol), are known to have potent antioxidant activity. Tumor necrosis factor-alpha (TNF) is found in human atheroma and produces oxygen-derived free radicals. These oxygen-derived free radicals may modify low density lipoproteins (LDL) and increase LDL binding in the artery wall. We asked: 1) does TNF increase LDL accumulation in the artery wall and 2) can the TNF-mediated increase in LDL accumulation be prevented by the antioxidant activity of estradiol? Carotid arteries from ovariectomized 3-month-old rats were removed and perfused with fluorescently labeled LDL and arterial LDL flux was measured using quantitative fluorescence microscopy. In six arteries, addition of TNF (10 ng/ml) to the perfusate resulted in a 2.3-fold increase in the rate of LDL accumulation (1.50 +/- 0.37 ng/min per cm2 vs. 3.38 +/- 0.48 ng/min per cm2; P < 0.01). Estradiol (65 pg/ml) and alpha-tocopherol (6 mg/L) both attenuated TNF-mediated LDL accumulation (P < 0.05), indicating that TNF may exert its effects on LDL accumulation through cellular production of oxygen-derived free radicals. These results support an antioxidant role for estradiol in the protection against LDL accumulation in the artery wall and subsequent progression of atherosclerosis.