Reduction In Endothelial Function Research Articles

Decreased vascular H2S production is associated with vascular oxidative stress in rats fed a high-fat western diet.

A Western-style high-fat diet is known to cause vascular dysfunction and oxidative stress. H2S contributes to the regulation of vascular function and acts as a vasoprotective molecule; however, the effects of high-fat diet on vascular H2S production and function are not known. The aim of this study was to investigate the effects of high-fat diet on vascular function and H2S production. Wistar hooded rats were fed a western diet (WD, 21% fat) or control rat chow (6% fat) for 12weeks. At the end of the experiment, the aorta was collected for assessing vascular function and NO and H2S bioavailability. Superoxide anion production was quantitated by lucigenin-enhanced chemiluminescence. The expression of NADPH oxidase subunit Nox2 and the H2S-producing protein cystathionine-γ-lyase (CSE) were examined by Western blotting. WD rats had significantly higher body weight and body fat than control (p<0.001). Endothelial function and NO bioavailability were significantly reduced in the WD group (p<0.05), but vascular smooth muscle cell function was unaffected. Vascular superoxide production and Nox2 expression were significantly increased in the aorta from WD rats. L-Cysteine-induced vasorelaxation was reduced in the WD group (p<0.05) and insensitive to the inhibition of the CSE. In addition, vascular H2S bioavailability and CSE expression were significantly reduced in the aorta from WD rats (p<0.01). These data show that fat feeding induces vascular oxidative stress and a reduction in endothelial function. Furthermore, there is a reduced capacity for both basal and stimulated vascular H2S production via CSE in fat fed rats.

Vascular and Endothelial Biology of Aging

Although aging is one of the greatest risk factors for vascular disease, very little is known regarding mechanisms that control the progression of vascular aging at the level of the endothelial cell. Endothelial dysfunction - a critical element of carotid artery and cerebrovascular disease - progresses with age, contributing to hypoperfusion, increased risk for ischemic stroke, and cognitive decline. Studies from several laboratories support the concept that age-induced endothelial dysfunction may occur earlier and be larger in magnitude in the cerebral circulation than in blood vessels outside of the brain. Thus, the circulationof the brain may be particularly sensitive to age-induced endothelial dysfunction. In relation to underlying mechanisms, angiotensin II type 1 receptors, NADPH oxidase, and oxidative stress appear to play a key role in age-related vascular dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-g (PPARg) exerts protective effects in the vasculature when pharmacologically activated. We recently examined the hypothesis that endothelial PPARg protects against vascular aging. We studied carotid arteries from adult and old transgenic mice with endothelial specific expression of a human dominant negative mutation in PPARg driven by the vascular cadherin promoter (designated E-V290M), along with non-transgenic littermates. Endothelial function was similar in arteries from adult non-transgenic and E-V290M mice as well as old non-transgenic mice. In contrast, there was a marked reduction in endothelial function in old E-V290M mice. This augmented endothelial dysfunction was not altered by inhibition of cyclooxygenase, but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of Rho kinase. Oxidant and inflammatory related mechanisms often interact. Vascular expression of interleukin-6, another mediator of vascular disease, was increased 1.6-fold in old non-transgenic mice, but almost 9-fold in old E-V290M mice. Expression of CDKN2A, a molecular marker of senescence, was ~two-fold greater in old E-V290M mice compared to controls. These findings provide the first evidence that senescence and age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARg through mechanisms that involve oxidative stress, inflammation, and Rho kinase. This critical role for endothelial PPARg has implications for vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease. DisclosuresNo relevant conflicts of interest to declare.

Acute dietary nitrate supplementation improves arterial endothelial function at high altitude: A double-blinded randomized controlled cross over study

IntroductionDietary nitrate (NO3−) supplementation serves as an exogenous source of nitrite (NO2−) and nitric oxide (NO) through the NO3− – NO2− – NO pathway, and may improve vascular functions during normoxia. The effects of NO3− supplementation in healthy lowlanders during hypobaric hypoxia are unknown. PurposeDetermine the effect of acute oral NO3−supplementation via beetroot juice (BJ) on endothelial function (flow mediated dilation; FMD) in lowlanders at 3700 m. MethodsFMD was measured using ultrasound and Doppler in the brachial artery of 11 healthy subjects (4 females, age 25 ± 5 yrs; height 1.8 ± 0.1 m, weight 72 ± 10 kg) sojourning to high altitude. In a randomized, double-blinded crossover study design, FMD was measured 3 h after drinking BJ (5.0 mmol NO3−) and placebo (PL; 0.003 mmol NO3−) supplementation at 3700 m, with a 24-h wash out period between tests. FMD was also measured without any BJ supplementation pre-trek at 1370 m, after 5 days at 4200 m and upon return to 1370 m after 4 weeks of altitude exposure (above 2500 m). The altitude exposure was interrupted by a decent to lower altitude where subjects spent two nights at 1370 m before returning to altitude again. ResultsTen subjects completed the NO3− supplementation. FMD (mean ± SD) pre-trek value was 6.53 ± 2.32% at 1370 m. At 3700 m FMD was reduced to 3.84 ± 1.31% (p < 0.01) after PL supplementation but was normalized after receiving BJ (5.77 ± 1.14% (p = 1.00). Eight of the subjects completed the interrupted 4-week altitude stay, and their FMD was lower at 4200 m (FMD 3.04 ± 2.22%) and at post-altitude exposure to 1370 m (FMD 3.91 ± 2.58%) compared to pre-trek FMD at 1370 m. ConclusionAcute dietary NO3−supplementation may abolish altitude-induced reduction in endothelial function, and can serve as a dietary strategy to ensure peripheral vascular function in lowland subjects entering high altitude environments.

6D.04

Objective: Increased potassium intake has been related to improved endothelial function and a high sodium intake is known to impair endothelial function. The effect of increasing potassium in the presence of high sodium in the postprandial state is not known. The aim was to determine the effect of increased potassium and increased sodium on post prandial endothelial function (as assessed by flow mediated dilatation (FMD)) and arterial compliance as assessed by pulse wave velocity (PWV) and augmentation index (AIx). Design and method: Thirty nine healthy, normotensive volunteers (age 37 ± 15 and BMI 23.0 ± 2.8) received a meal with 3.1mmol potassium and 65mmol sodium (LKHN), a meal with 38mmol potassium and 65mmol sodium (HKHN) and a control meal (LKLN) with 5.5mmol sodium and 3.1mmol potassium on three separate occasions in a randomized order. FMD, PWV, AIx and BP were measured while participants were fasting and at 30, 60, 90 and 120 minutes after the meal. Repeated-measures ANOVA was used to assess the effects of the meal type on the dependent variables over time. Results: The addition of potassium (HKHN meal) significantly attenuated the post meal decrease in FMD when compared to the high sodium meal (p < 0.05 meal by time) (Figure 1). FMD was significantly lower following the LKHN meal when compared to the HKHN meal at 30 minutes (p < 0.05). AIx decreased after all meals (p < 0.05). There were no significant differences in AIx, PWV or BP between treatments over time.Conclusions: The addition of potassium to a high sodium meal attenuates the post meal reduction in endothelial function as assessed by FMD. There were no between meal differences on PWV and AIx.

Effect of sodium and potassium supplementation on vascular and endothelial function: a randomized controlled trial

It is known that increased potassium and reduced sodium intakes can improve postprandial endothelial function. However, the effect of increasing potassium in the presence of high sodium in the postprandial state is not known. We aimed to determine the effect of high potassium and high sodium on postprandial endothelial function as assessed by using flow-mediated dilatation (FMD) and arterial compliance as assessed by using pulse wave velocity (PWV) and central augmentation index (AIx). Thirty-nine healthy, normotensive volunteers [21 women and 18 men; mean ± SD age: 37 ± 15 y; BMI (in kg/m(2)): 23.0 ± 2.8] received a meal with 3 mmol K and 65 mmol Na (low-potassium, high-sodium meal (LKHN)], a meal with 38 mmol K and 65 mmol Na [high-potassium, high-sodium meal (HKHN)], and a control meal with 3 mmol K and 6 mmol Na (low-potassium, low-sodium meal) on 3 separate occasions in a randomized crossover trial. Brachial artery FMD, carotid-femoral PWV, central AIx, and blood pressure (BP) were measured while participants were fasting and at 30, 60, 90, and 120 min after meals. Compared with the LKHN, the addition of potassium (HKHN) significantly attenuated the postmeal decrease in FMD (P-meal by time interaction < 0.05). FMD was significantly lower after the LKHN than after the HKHN at 30 min (P < 0.01). AIx decreased after all meals (P < 0.05). There were no significant differences in AIx, PWV, or BP between treatments over time. The addition of potassium to a high-sodium meal attenuates the sodium-induced postmeal reduction in endothelial function as assessed by FMD. This trial was registered at http://www.anzctr.org.au/ as ACTRN12613000772741.

Circuit resistance training attenuates acute exertion-induced reductions in arterial function but not inflammation in obese women.

Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Eighteen obese [body mass index (BMI) 30.0-40.0 kg · m(-2)] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation.

High Trans‐Fat but not Saturated Fat Beverage Causes an Acute Reduction in Vascular Endothelial Function and Insulin Sensitivity in Humans

A diet high in trans‐fatty acids (TFA) is associated with increased cardiovascular disease risk, mediated in part from dyslipidemia, endothelial dysfunction and insulin resistance. A high‐fat meal causes a transient (3‐4 hrs postprandial) reduction in endothelial function and insulin sensitivity, but studies are often confounded by meals high in carbohydrate, saturated fatty acids (SFAs) and/or TFAs. We hypothesized that a beverage high in TFA (but low in carbohydrate, SFA) would cause a larger acute reduction in endothelial function (brachial artery flow‐mediated dilation, FMD) and insulin sensitivity compared with SFA (but low in carbohydrate, TFA). Healthy non‐obese adults (n=11; 9M/2F; age=47±3 yrs) ingested a warm beverage (520kcal, 56g total fat, 5g carbohydrate), high in either TFA (42%TFA, 23%SFA; partially hydrogenated soybean oil), SFA (88%SFA, 0.2%TFA; coconut oil) or placebo (2g total fat, 5g carbohydrate) in a randomized, cross‐over study. TFA (0.19±0.02 to 0.06±0.03mm, P&lt;0.01), but not SFA (0.14±0.03 vs. 0.11±0.04mm, P=0.49) or placebo (0.08±0.04 to 0.062±0.03mm, P=0.52), caused a reduction in FMD at 3‐4 hours (P&lt;0.01 for time; p=0.02 for interaction effects). Postprandial glucose was reduced across groups (P&lt;0.001), whereas the homeostasis model of insulin resistance (HOMA‐IR) decreased in SFA and placebo (P&lt;0.001) but not TFA (1.4±0.2 vs 1.2±0.2, P=0.08, interaction P=0.02). These data suggest that ingestion of a beverage high in TFA, but not SFA, results in an acute reduction in endothelial function and insulin sensitivity in healthy adults. Supported by NIH 5T32HL007638‐28, 5T32HL007121‐3, U54TR001013.

Abstract 464: Effects of Increased Potassium and Sodium on Endothelial Function: A Pilot Study

Background and aim: Increased potassium intake has been related to reduced blood pressure (BP) and improved endothelial function. High sodium intake increases BP and impairs endothelial function. The effect of increasing potassium in the presence of high dietary sodium is not known. The aim was to determine the effect of increased potassium and increased sodium on post prandial endothelial function, as assessed by flow mediated dilatation (FMD). Materials and methods: Eighteen healthy, normotensive volunteers (age 41±16 and BMI 23.0±2.7) received a meal with 3.1mmol potassium and 65mmol sodium (LKHNa), a meal with 38mmol potassium and 65mmol sodium (HKHNa) and a control meal (LKLNa) with 5.5mmol sodium and 3.1mmol potassium on three separate occasions in a randomized order. FMD, pulse wave velocity (PWV), augmentation index (AI) and BP were measured while participants were fasting and at 30, 60, 90 and 120 minutes after the meal. Results: The LKHNa meal produced a significant reduction in FMD at 90 minutes when compared to the LKLNa control meal (p&lt;0.01). The addition of potassium (HKHNa) significantly attenuated the post meal decrease in FMD when compared to the high sodium meal (p&lt;0.05) at 90 minutes (Figure 1) . There was no significant differences in PWV, AI, or BP. The study will continue until n=40. Conclusions: The addition of potassium to a high sodium meal may attenuate the post meal reduction in endothelial function as assessed by FMD. Increases in sodium and potassium do not appear to effect PWV, AI or BP in the postprandial state. Additional data collection will continue to elucidate the effect of increased potassium in the presence of high sodium.

Exploration of the composition and sources of urban fine particulate matter associated with same-day cardiovascular health effects in Dearborn, Michigan.

The objective was to explore associations of chemical components and source factors of ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μm; PM2.5) with cardiovascular (CV) changes following same-day exposure to ambient PM2.5. Twenty-five healthy adults living in rural Michigan were exposed to ambient air in an urban/industrial community for 4 to 5 h daily for five consecutive days. CV health outcomes were measured 1-2 h post exposure. Contributing emission sources were identified via positive matrix factorization. We examined associations between PM2.5 mass, composition and source factors, and same-day changes in CV outcomes using mixed-model analyses. PM2.5 mass (10.8 ± 6.8 μg/m(3)), even at low ambient levels, was significantly associated with increased heart rate (HR). Trace elements as well as secondary aerosol, diesel/urban dust and iron/steel manufacturing factors potentially explained the HR changes. However, trace element analysis demonstrated additional associations with other CV responses including changes in blood pressure (BP), arterial compliance, autonomic balance and trends toward reductions in endothelial function. Two factors were related to BP changes (diesel/urban dust, motor vehicle) and trends toward impaired endothelial function (diesel/urban dust). This study indicates composition of PM2.5 and its sources may contribute to CV health effects independently of PM2.5 mass.

B-26 Free Communication/Poster - Cardiorespiratory Fitness

Introduction: Sitting time is associated with multiple cardiovascular and metabolic disease risk factors. Breaking sitting time has been reported to have beneficial associations with cardiovascular and metabolic risk. The direct effects breaking sitting time on endothelial function, which is cross-sectionally and prospectively associated with risk of cardiovascular disease, are unknown. PURPOSE: The purpose of this study was to examine the direct effects of breaking sitting time on femoral artery endothelial function. We hypothesized that breaks in sitting time will prevent the attenuation in endothelial function associated with prolonged sitting. METHODS: Eleven non-obese, healthy men (23.36±3.23 yrs) participated in two randomized 3 hr sitting trials. Subjects reported to the lab in a 6 hr fasted state. Subjects sat on a cushioned Chair: with their legs perpendicular to the floor, with feet flat on the ground. In the prolonged sitting (SIT) trial, subjects were seated for 3 hrs without moving their lower extremities. In the breaking sitting time trial (ACT), subjects sat similar to the SIT trial, but walked on a treadmill for 5 min at 2 mph at 0:30 min, 1:30 hr and 2:30 hr. Superficial femoral artery (SFA) flow mediated dilation (FMD) was assessed as a measure of endothelial function at baseline, 1hr, 2hr and 3hr in each trial. Descriptive statistics were performed for subject characteristics and paired sample t-tests were performed to examine the differences at each time point between SIT and ACT trial. RESULTS: There was no significant difference between the SFA FMD% at baseline (SIT: 4.82±3.95; ACT: 4.49±2.29, P=.776). However there were significant differences at 1 hr (SIT 0.47±0.88; ACT 5.04±2.85, P=0.001), 2hr (SIT 1.64±1.16; ACT 5.28± 5.05, P=0.045) and 3hr (SIT2.26±2.25; ACT 6.91±4.5, P=0.004) with an effect of ACT to prevent the reduction in FMD associated with SIT. CONCLUSION: Three hours of continuous sitting resulted in a significant impairment in superficial femoral artery endothelial function. When breaks with brief modest activity were introduced during the sitting time, this reduction in endothelial function was prevented. Breaking sitting time may be a physiologically beneficial cost effective way of maintaining vascular health in the sedentary population.

Brief Exposure to Secondhand Smoke Reversibly Impairs Endothelial Vasodilatory Function

We sought to determine the effects of brief exposures to low concentrations of tobacco secondhand smoke (SHS) on arterial flow-mediated dilation (FMD, a nitric oxide-dependent measure of vascular endothelial function), in a controlled animal model never before exposed to smoke. In humans, SHS exposure for 30 min impairs FMD. It is important to gain a better understanding of the acute effects of exposure to SHS at low concentrations and for brief periods of time. We measured changes in FMD in rats exposed to a range of real-world levels of SHS for durations of 30 min, 10 min, 1 min, and 4 breaths (roughly 15 s). We observed a dose-response relationship between SHS particle concentration over 30 min and post-exposure impairment of FMD, which was linear through the range typically encountered in smoky restaurants and then saturated at higher concentrations. One min of exposure to SHS at moderate concentrations was sufficient to impair FMD. Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1 min of SHS exposure can cause reduction of endothelial function.

Uric Acid and Coronary Collateral Circulation

Coronary collateral (CC) artery development is usually attributed to ischemia, but these anastomotic channels are also present in individuals who do not have coronary artery disease (CAD). The CCs are present in one-fourth of the patients with normal coronary arteries or nonobstructive CAD. Currently, there is no noninvasive method for evaluating CC circulation in humans. The most widely used strategy is visual assessment of collateral arteries as described by Rentrop et al. This method involves balloon occlusion of the contralateral coronary artery, which is rarely performed. In clinical practice, this method is applied without occluding the contralateral vessels. As a result, underestimation of collateralization is inevitable. Other limitations of this visual method include observer variability, influence by the blood pressure, and the force of contrast injection as well as the duration of filming. The most accurate assessment could be obtained by measuring the pressure-derived collateral flow index. Several clinical and angiographic variables including the degree of coronary stenosis, proximal lesion location, longer duration of symptoms, and occlusion as well as resting bradycardia have been reported as variables that correlated with the degree of collateralization. Also, in patients without CAD, the baseline heart rate has been described as the main predictor of collateralization. The most important trigger for collateral growth is tangential (radial) fluid shear stress at the endothelial level with the recruitment of bone marrow-derived mononuclear cells. It is a remodeling process of preexisting small collateral arterioles rather than the growth of new capillary vessels, which is induced by ischemia. Collateral growth is induced by fluid shear stress in preformed collateral vessels caused by a pressure gradient between the area proximal to a coronary stenosis and the low-pressure poststenotic area. The CCs play a role in preserving myocardial function, limiting infarct size, and increasing survival. However, a meta-analysis showed that a well-developed collateral circulation was a risk factor for restenosis after coronary revascularization. In humans, uric acid (UA) is generated from purine catabolism with the conversion of hypoxanthine to xanthine and of xanthine to UA by the enzyme xanthine oxidoreductase. It is further oxidized to allantoin in most species except humans and some higher primates who lack uricase. Therefore, serum UA (SUA) levels in humans are appreciably higher than in other mammals. Because of this difference in urate metabolism, the results of animal studies can be difficult to interpret. Also, different methods of measuring collateral flow may be applied in animal studies. Many patients with CAD use at least 1 drug that can influence SUA levels (eg, aspirin, statins, fibrates, and some antihypertensive agents). The SUA levels are higher in men than in women at all ages due to gender steroids. Sumino et al showed that hormone replacement therapy in postmenopausal women was associated with a significant reduction in SUA level. Also, dietary, environmental, and genetic factors are important determinants of SUA levels. It is important to note that UA is a potent antioxidant, but it can also be a prooxidant if the level is >6 mg/dL in women and 6.5 to 7.0 mg/dL in men. Therefore, elevated SUA level might be an indicator of increased burden of oxidant attack. Besides its dual oxidant effect, if UA is a harmful product, why do our kidneys recover 90% of filtered UA instead of eliminating it? Despite the antioxidant properties of UA, several studies have indicated that high SUA levels are associated with several disorders, including CAD, peripheral arterial disease, heart failure, metabolic syndrome, hypertension, and stroke. These associations have been mainly attributed to upregulation of renin release and the subsequent cascade-related reduction in endothelial function. However, instead of proven causal associations, possible explanations with small study groups could be reverse causality. For example, preclinical atherosclerosis could lead to higher levels of SUA. In contrast, experts from the Framingham Heart Study group have reported no association between the SUA and the cardiovascular disease. In a recently published study, Palmer et al investigated the association of plasma UA with CAD and hypertension using Mendelian randomization. They found no evidence of a causal effect of UA or hyperuricemia on the risk of CAD and hypertension. Recently, some studies have demonstrated an association between SUA and CC development in patients with CAD and

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD(+/+)) and manganese SOD heterozygous haploinsufficient (MnSOD(+/-)) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16(ink4a), a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD(+/+) and MnSOD(+/-) mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD(+/+) and MnSOD(+/-) mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD(+/+) mice but significantly impaired endothelial function in MnSOD(+/-) mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.

Aging compounds western diet-associated large artery endothelial dysfunction in mice: Prevention by voluntary aerobic exercise

We tested the hypothesis that aging will exacerbate the negative vascular consequences of exposure to a common physiological stressor, i.e., consumption of a “western” (high fat/high sucrose) diet (WD), by inducing superoxide-associated reductions in nitric oxide (NO) bioavailability, and that this would be prevented by voluntary aerobic exercise. Incremental stiffness and endothelium-dependent dilation (EDD) were measured in the carotid arteries of young (5.4±0.3mo, N=20) and old (30.4±0.2mo, N=19) male B6D2F1 mice fed normal chow (NC: 17% fat, 0% sucrose) or a western diet (40% fat, 19% sucrose) and housed in either standard cages or cages equipped with running wheels for 10–14weeks. Incremental stiffness was higher in old NC (P<0.05) and both young (P<0.01) and old (P<0.01) WD fed mice compared with young NC mice, but WD did not further increase stiffness in the old mice. In cage control mice, maximal EDD was 17% lower in both NC fed old mice and young WD fed mice (P<0.05). Consumption of WD by old mice led to a further 20% reduction in maximal EDD (P<0.05). Incremental stiffness was 28% lower and maximal EDD was 38% greater in old WD fed mice with access to running wheels vs. old WD fed control mice (P<0.05) and not different from young NC fed controls. Wheel running also tended to improve maximal EDD (+9%, P=0.11), but not incremental stiffness in young WD fed mice. Ex vivo treatment with the superoxide scavenger TEMPOL and NO inhibitor l-NAME abolished these respective effects of age, WD and voluntary running on EDD. Ingestion of a WD induces similar degrees of endothelial dysfunction in old and young adult B6D2F1 mice, and these effects are mediated by a superoxide-dependent impairment of NO bioavailability. However, the combination of old age and WD, a common occurrence in our aging society, results in a marked, additive reduction in endothelial function. Importantly, regular voluntary aerobic exercise reduces arterial stiffness and protects against the adverse influence of WD on endothelial function in old animals by preventing superoxide suppression of NO. These findings may have important implications for arterial aging and the prevention of age-associated cardiovascular diseases.

Randomized Trial to Evaluate Cardiometabolic and Endothelial Function in Patients with Plasma HIV-1 RNA Suppression Switching to Darunavir/Ritonavir with or without Nucleoside Analogues

Background: We performed a study to evaluate change in cardiometabolic and endothelial function in HIV-infected patients switching to darunavir/ritonavir (DRV/r) monotherapy versus triple therapy. Methods: The MONARCH trial recruited 30 patients who were taking triple combination therapy and with HIV RNA<40 copies/ mL. Patients were randomized to either DRV/r 800/100 mg once daily (OD) monotherapy or DRV/r 800/100 mg OD plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). The primary objective was to assess endothelial function change from baseline to 24 and 48 weeks in brachial artery flow-mediated dilation (FMD) test; changes in endothelial precursor cells (EPCs) and circulating endothelial cells (CECs) were secondary objectives. Results: At baseline, the median age of participants was 43 years, 77% were men, and median CD4 cell count was 585 cells/μL. The median FMD (%) decreased in both arms in the study period (P > .05), with no statistically significant difference between arms (10.7% at baseline and 6.7% at week 48 in the DRV/r + 2 NRTIs arm; 11.1% at baseline and 8.8% at week 48 in the DRV/r arm). The changes at week 48 were similar in the 2 arms for EPCs and CECs. Total cholesterol and low-density lipoprotein (LDL) cholesterol showed larger rises to week 48 in the DRV/r arm monotherapy group than in the triple-therapy group (+26 vs +9 mg/dL for total cholesterol and +14 vs +5 mg/dL for LDL cholesterol). Conclusions: In the MONARCH trial, switching from triple combination treatment to DRV/r, with or without nucleoside analogues, did not translate into clinically meaningful reductions in endothelial function as measured by FMD.

Nutritionally essential amino acids and metabolic signaling in aging

Aging is associated with a gradual decline in skeletal muscle mass and strength leading to increased risk for functional impairments. Although basal rates of protein synthesis and degradation are largely unaffected with age, the sensitivity of older muscle cells to the anabolic actions of essential amino acids appears to decline. The major pathway through which essential amino acids induce anabolic responses involves the mammalian target of rapamycin (mTOR) Complex 1, a signaling pathway that is especially sensitive to regulation by the branched chain amino acid leucine. Recent evidence suggests that muscle of older individuals require increasing concentrations of leucine to maintain robust anabolic responses through the mTOR pathway. While the exact mechanisms for the age-related alterations in nutritional signaling through the mTOR pathway remain elusive, there is increasing evidence that decreased sensitivity to insulin action, reductions in endothelial function, and increased oxidative stress may be underlying factors in this decrease in anabolic sensitivity. Ensuring adequate nutrition, including sources of high quality protein, and promoting regular physical activity will remain among the frontline defenses against the onset of sarcopenia in older individuals.

Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment

BackgroundSeveral studies suggest an increase of oxidative stress and a reduction of endothelial function in obstructive sleep apnoea syndrome (OSAS). We assessed the association between OSAS, endothelial dysfunction and oxidative stress. Further aim was to evaluate the effect of nasal continuous positive airway pressure (nCPAP) on oxidative stress and arterial dysfunction.MethodsWe studied 138 consecutive patients with heavy snoring and possible OSAS. Patients underwent unattended overnight home polysomnography. Ten patients with severe OSAS were revaluated after 6 months of nCPAP therapy. To assess oxidative stress in vivo, we measured urinary 8-iso-PGF2α and serum levels of soluble NOX2-derived peptide (sNOX2-dp). Serum levels of nitrite/nitrate (NOx) were also determined. Flow-mediated brachial artery dilation (FMD) was measured to asses endothelial function.ResultsPatients with severe OSAS had higher urinary 8-iso-PGF2α (p<0.001) and serum NOX2 and lower NOx. A negative association was observed between FMD and OSA severity. Apnea/hypopnea index was significantly correlated with the indices of central obesity and with urinary 8-isoprostanes (r=0.298, p<0.001). The metabolic syndrome (t=-4.63, p<0.001) and urinary 8-isoprostanes (t=-2.02, p<0.05) were the only independent predictors of FMD. After 6-months nCPAP treatment, a significant decrease of serum NOX2, (p<0.005) and urinary 8-iso-PGF2α (p<0.01) was observed, while serum NOx showed only a minor increase. A statistically significant increase of FMD was observed (from 3.6% to 7.0%).ConclusionsThe results of our study indicate that patients with OSAS and cardiometabolic comorbidities have increased oxidative stress and arterial dysfunction that are partially reversed by nCPAP treatment.

Cardiopulmonary and endothelial effects of metformin treatment in an insulin resistant population

Insulin resistance (IR) is considered a primary etiologic factor in the development of cardiac dysfunction. A high prevalence of IR has been found in the non-ischemic heart failure population. It predates the development of the disease, and independently defines a worse prognosis [1]. Several studies have shown that a reduction in endothelial function [2] may represent the link between IR and decline in cardiovascular performance. Treatment with metformin has been reported to prevent the above-mentioned cardiac abnormalities [3] and the evolution of IR diabetes [4].

Tacrolimus-Induced Hypertension

See related article, pp 1167–1175 Hypertension associated with solid-organ transplantation is of major clinical importance, because the degree of posttransplant hypertension has been shown to correlate with reductions in graft viability and survival.1,–,3 Effective blood pressure control with antihypertensives has been shown to enhance graft survival and reduce the risk of future cardiovascular disease and events in transplant recipients.3 The etiology of posttransplant hypertension is varied; however, hypertension produced by immunosuppressant therapy is an important cause of posttransplant-related hypertension. Tacrolimus (FK506) and cyclosporine A are 2 common immunosuppressants that have been shown to affect blood pressure. Thus, elucidation of mechanisms that contribute to posttransplant hypertension has major clinical implications. In general, the type of immune response evoked by a particular set of antigens, such as that associated with organ transplantation, depends on the expansion of specific T-lymphocyte (T-cell) subsets, as well as the duration of antigen exposure, which, in the case of organ transplantation, is life long. Tacrolimus and cyclosporine A limit the immune response via inhibition of calcineurin activity, through similar but slightly different mechanisms. With tacrolimus, the mechanism of calcineurin inhibition involves tacrolimus binding to its cytosolic binding partner, the ubiquitously expressed immunophilin FKBP12. Tacrolimus/FKBP12, along with calcium and calmodulin, forms a complex with calcineurin, thereby inhibiting calcineurin's phosphatase activity. Calcineurin signaling has been shown to regulate expression of a number of cytokines, including interleukin (IL)-2, IL-3, IL-4, and interferon-γ, as well as expression of the IL-2 receptor, which have been implicated in T-cell activation.4 For example, reducing IL-2 signaling with tacrolimus is important in limiting the immune response, because IL-2 promotes the expansion of cytotoxic T cells and has been shown to play an important role in immunologic memory. In this issue of Hypertension , Chiasson et al5 report …

Study The Relationship Between Intercellular Adhesion Molecules( ICAM) And Insulin Resistance Among Type 2 Egyptian Diabetic Patients With Nephropathy

Type 2 Diabetes is the common form of diabetes accounting for 90% of diabetic cases. As the incidence of type 2 diabetes is increasing the development of diabetic nephropathy. Nephropathy is one of the serious long-term complications of diabetes and may develop in 30-40% of diabetes mellitus patients. Endothelial inflammation has been implicated in the development of diabetic nephropathy. Type 2 diabetic patients usually present endothelial dysfunction. Reduction of endothelial function in type 2 diabetic patients stimulates inflammation and increases the levels of circulating soluble adhesion molecules (Intercellular adhesion molecules (ICAM)). Cell adhesion molecules are important in promoting the inflammatory response. The aim of the present study is to determineplasma concentration of ICAM-1 as a marker for endothelial activation among type 2 diabetic patients with or without nephropathy (as tool in early diagnosis of nephropathy as major diabetic complications) also to explore the relationship between plasma level of ICAM-1 and insulin resistance in the studied patients. This study includes 70 subjects; 50 patients with type 2 diabetes mellitus were divided into two groups; First group consisted of 20 type 2 diabetic patients without complications. The second group comprised 30 type 2 diabetic patients with nephropathy. The third group (healthy controls) includes 20 non-diabetic subjects without a family history of diabetes mellitus. The results show that the mean sICAM-1 level was significantly higher in the diabetic patients with nephropathy than in those without nephropathy and in the controls .Also insulin level increase in diabetic patients than control. In addition positivecorrelation between ICAM-1 and insulin resistance in studied subjects. It can be concluded that the association between ICAM-1 expression and insulin resistance found in this study is consistent with clinical evidence relating insulin resistance and inflammation and high levels of sICAM-1 suggest that sICAM-1 may play a role in the development of nephropathy in patients with type 2 diabetes mellitus and can be use as a marker for early diagnosis of nephropathy as a major diabetic complications.Keywords: cell adhesion molecules, type 2 diabetes mellitus,nephropathy, insulin resistance, ICAM-1