Saluisn-ß contributes to endothelial dysfunction in monocrotaline-induced pulmonary arterial hypertensive rats.

BACKGROUND: The endothelial dysfunction and the consequent attenuated pulmonary vasodilatation are the major causes of elevated pulmonary arterial resistance and pressure in pulmonary arterial hypertension (PAH). Current study aimed to explore the effects of a TOR2A gene product, salusin-ß, on endothelium-dependent vascular relaxation and the progression of PAH in monocrotaline (MCT)-induced PAH rats as well as the relevant signaling pathway. METHODS: Acetylcholine (ACh)-induced dose-dependent relaxation was used to evaluate the endothelium-dependent vasodilatation function. RESULTS: The salusin-ß level in plasma and pulmonary artery (PA) in MCT-PAH rats were significantly increased, while the ACh-induced endothelium-dependent vasodilatation was attenuated. After salusin-ß incubation or overexpression of salusin-ß gene, the endothelium-dependent relaxation was further deteriorated, while anti-salusin-ß IgG incubation or knockdown of salusin-ß improved it in PAH rats. The superoxide anions scavenger NAC or the antioxidant apocynin inhibited the effect of salusin-ß, while the SOD inhibitor DETC further enhanced it. The nitric oxide (NO) synthase inhibitor L-NAME almost blocked the effect of anti-salusin-ß IgG. Silencing of salusin-ß in PAH rats decreased right ventricular (RV) systolic pressure, RV hypertrophy index, NAD(P)H oxidase activity and ROS level, and increased the eNOS activity and NO level of PA. Overexpression of salusin-ß played opposite roles. CONCLUSIONS: The elevated saluisn-ß level in PAH rats plays important roles in the reduction of endothelium-dependent vasodilatation and participates in the progression of PAH through stimulating NAD(P)H oxidase-ROS production and inhibiting eNOS-NO release.

Global endothelial function assessment using pulse wave analysis in hypercholesterolemia

To compare global endothelial function assessed by pulse wave analysis (PWA) using the ratio of endothelium dependent vasodilatation (EDV) to endothelium independent vasodilatation (EIV) in patients with hypercholesterolemia and controls. 92 subjects [46 hypercholesterolemics, 46 controls] were studied at standardized conditions. Baseline augmentation index (AIx) was assessed followed by the administration of 0.5 mg sublingual nitroglycerine, an endothelium independent vasodilator. AIx was assessed and the maximum change in AIx after nitroglycerine was recorded as EIV. After a washout period of 30 minutes, 400 µg of inhaled salbutamol, an endothelium dependent vasodilator was administered. AIx was assessed again and the maximum change in AIx after salbutamol was recorded as EDV. Global endothelial function was calculated as EDV:EIV ratio. EDV and EIV in patients with hypercholesterolemia compared to controls were 2.97 ± 3.95 and 6.65 ± 3.80 (p<0.001); and 13.41 ± 4.57 and 15.88 ± 4.78 (p=0.01) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls; 0.21 ± 0.38 and 0.44 ± 0.24 (p<0.001) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls. PWA is a potential clinical tool to assess global endothelial function in patients with hypercholesterole

Lifelong voluntary aerobic exercise prevents age- and Western diet- induced vascular dysfunction, mitochondrial oxidative stress and inflammation in mice.

KEY POINTS: The results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Ageing impaired nitric oxide-mediated EDD (peak EDD 88 ± 12% 6 months P = 0.003 vs. 59 ± 9% 27 months NC-SED), which was accelerated by WD (60 ± 18% 6 months WD-SED). In NC mice, aPWV increased 32% with age (423 ± 13 cm/s at 24 months P < 0.001 vs. 321 ± 12 cm/s at 6 months) and absolute values were an additional ∼10% higher at any age in WD mice (P = 0.042 vs. NC-SED). Increases in aPWV with age in NC and WD mice were associated with 30-65% increases in aortic intrinsic wall stiffness (6 vs. 19-27 months, P = 0.007). Lifelong aerobic exercise prevented age- and WD-related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms.

Ageing augments ß-adrenergic cutaneous vasodilatation differently in men and women, with no effect on ß-adrenergic sweating.

NEW FINDINGS: What is the central question of this study? ß-Adrenergic receptor activation modulates cutaneous vasodilatation and sweating in young adults. In this study, we assessed whether age-related differences in ß-adrenergic regulation of these responses exist and whether they differ between men and women. What is the main finding and its importance? We showed that ageing augmented ß-adrenergic cutaneous vasodilatation, although the pattern of response differed between men and women. Ageing had no effect on ß-adrenergic sweating in men or women. Our findings advance our understanding of age-related changes in the regulation of cutaneous vasodilatation and sweating and provide new directions for research on the significance of enhanced ß-adrenergic cutaneous vasodilatation in older adults. ABSTRACT: ß-Adrenergic receptor agonists, such as isoprenaline, can induce cutaneous vasodilatation and sweating in young adults. Given that cutaneous vasodilatation and sweating responses to whole-body heating and to pharmacological agonists, such as acetylcholine, ATP and nicotine, can differ in older adults, we assessed whether ageing also modulates ß-adrenergic cutaneous vasodilatation and sweating and whether responses differ between men and women. In the context of the latter, prior reports showed that the effects of ageing on cutaneous vasodilatation (evoked with ATP and nicotine) and sweating (stimulated by acetylcholine) were sex dependent. Thus, in the present study, we assessed the role of ß-adrenergic receptor activation on forearm cutaneous vasodilatation and sweating in 11 young men (24 ± 4 years of age), 11 young women (23 ± 5 years of age), 11 older men (61 ± 8 years of age) and 11 older women (60 ± 8 years of age). Initially, a high dose (100 µm) of isoprenaline was administered via intradermal microdialysis for 5 min to induce maximal ß-adrenergic sweating. Approximately 60 min after the washout period, three incremental doses of isoprenaline were administered (1, 10 and 100 µm, each for 25 min) to assess dose-dependent cutaneous vasodilatation. Isoprenaline-mediated cutaneous vasodilatation was greater in both older men and older women relative to their young counterparts. Augmented cutaneous vasodilatory responses were observed at 1 and 10 µm in women and at 100 µm in men. Isoprenaline-mediated sweating was unaffected by ageing, regardless of sex. We show that ageing augments ß-adrenergic cutaneous vasodilatation differently in men and women, without influencing ß-adrenergic sweating.

Ageing augments nicotinic and adenosine triphosphate-induced, but not muscarinic, cutaneous vasodilatation in women.

NEW FINDINGS: What is the central question of this study? Does ageing augment muscarinic, nicotinic and/or ATP-mediated cutaneous vasodilatation in women? What is the main finding and its importance? Ageing augments nicotinic and ATP-induced, but not muscarinic, cutaneous vasodilatation in women. This will stimulate future studies assessing the pathophysiological significance of the augmented microvascular responsiveness in older women compared to their young counterparts. ABSTRACT: We previously reported that ageing attenuates adenosine triphosphate (ATP)-induced, but not muscarinic and nicotinic, cutaneous vasodilatation in men, and that ageing may augment cutaneous vascular responses in women. In the present study, we evaluated the hypothesis that ageing augments muscarinic, nicotinic and/or ATP-mediated cutaneous vasodilatation in healthy women. In 11 young (23 ± 5 years) and 11 older (60 ± 8 years) women, cutaneous vascular conductance was evaluated at three forearm skin sites that were perfused with (1) methacholine (muscarinic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mm), (2) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mm), or (3) ATP (purinergic receptor agonist, 5 doses: 0.03, 0.3, 3, 30, 300 mm). Each agonist was administered for 25 min per dose. Methacholine-induced increases in cutaneous vascular conductance were not different between groups at all doses (all P > 0.05). However, a nicotine-induced elevation in cutaneous vascular conductance at the lowest concentration (1.2 mm) was greater in older vs. young women (43 ± 15 vs. 26 ± 10%max, P = 0.04). ATP-induced increases in cutaneous vascular conductance at moderate and high doses (3 and 30 mm) were also greater in older relative to young women (3 mm, 44 ± 11 vs. 28 ± 10%max, P = 0.02; 30 mm, 83 ± 14 vs. 64 ± 17%max, P = 0.05). Therefore, ageing augments nicotinic and ATP-induced, but not muscarinic, cutaneous vasodilatation in women.

Diagnostic Approach to Patients with Stable Angina and No Obstructive Coronary Arteries.

The diagnosis of microvascular angina (MVA) is usually considered in patients presenting with angina symptoms and evidence of MI on non-invasive stress tests but normal coronary arteries at angiography. A definitive diagnosis of MVA, however, would require the presence of coronary microvascular dysfunction. Several invasive (e.g. intracoronary Doppler wire recording and thermodilution) and non-invasive (e.g. PET, cardiac MRI, transthoracic Doppler echocardiography) methods can be applied to obtain a diagnosis. Both endothelium-dependent and -independent coronary microvascular dilator function, as well as increased microvascular constrictor activity, should be investigated. The main issues in the assessment of clinical and diagnostic findings in patients with suspected MVA are discussed and a diagnostic approach is suggested.

The association between near-infrared spectroscopy assessment of microvascular reactivity and flow-mediated dilation is disrupted in individuals at high risk for cardiovascular disease.

OBJECTIVE: This study aimed to evaluate the correlation between the NIRS-derived reperfusion slope and %FMD in the arm of healthy and at high risk for CVD individuals. METHODS: Twelve healthy (24 ± 4 years) and twelve at high risk for cardiovascular disease (65 ± 11 years) individuals participated in the study. The individuals were submitted to a conduit artery FMD followed by a NIRS-VOT microvascular function test in the arm. Microvascular responsiveness was calculated as the forearm reperfusion slope, and macrovascular function was assessed as the percent of change in FMD (%FMD) of the brachial artery. RESULTS: There was a significant correlation between reperfusion slope and %FMD (R = 0.61, P < 0.05) in the healthy group; however, no significant correlation between FMD and reperfusion slope (R = -0.21, P > 0.05) was found in individuals at high risk for CVD. CONCLUSION: The correlation between NIRS-derived reperfusion slope and %FMD was disrupted in the arm of individuals at high risk for cardiovascular disease compared to healthy individuals. The findings of the present study reinforce the importance of examining vascular function at microvasculature and conduit artery level, especially in populations with risk factors for CVD.

Shear stress sensitizes TRPV4 in endothelium-dependent vasodilatation.

The aim of this study was to better understand the role of TRPV4 in the regulation of blood vessel dilatation by blood flow and activation of GPCRs. Using pressure myography, the dilator responses to the TRPV4 agonist GSK1016790A and to acetylcholine, were examined in rat cremaster arterioles exposed to either no shear stress or to 200 µl/min flow for 6 min. In control vessels GSK1016709A caused vasodilatation (pEC50 7.73 ±â€¯0.12 M, ΔDmax 97 ±â€¯3%) which was significantly attenuated by the TRPV4 antagonists GSK2193874 (100 nM) (pEC50 6.19 ±â€¯0.11 M, p < 0.05) and HC067047 (300 nM) (pEC50 6.44 ±â€¯0.12 M) and abolished by removal of the endothelium. Shear conditioned arterioles were significantly more sensitive to GSK1016790A (pEC50 8.34 ±â€¯0.11, p < 0.05). Acetylcholine-induced vasodilatation (pEC50 7.02 ±â€¯0.07 M, ΔDmax 93 ±â€¯2%) was not affected by shear forces (pEC50 7.08 ±â€¯0.07 M, ΔDmax 95 ±â€¯1%). The dilator response to acetylcholine was unaffected by the TRPV4 antagonist GSK2193874 in control arterioles (pEC50 7.24 ±â€¯0.07 M, ΔDmax 97 ±â€¯2%). However, in shear treated arterioles, the acetylcholine-response was significantly attenuated by GSK2193874 (pEC50 6.25 ±â€¯0.12 M, p < 0.05) indicating an induced interaction between TRPV4 and muscarinic receptors. TRPV4 antibodies localized TRPV4 to the endothelium and shear stress had no effect on its localisation. Finally, agonist activation of the M3 muscarinic receptor opened TRPV4 in HEK293 cells. We concluded that shear stress increases endothelial TRPV4 agonist sensitivity and links TRPV4 activation to muscarinic receptor mediated endothelium-dependent vasodilatation, providing strong evidence that blood flow modulates downstream signalling from at least one but not all GPCRs expressed in the endothelium.

Type 2 diabetes specifically attenuates purinergic skin vasodilatation without affecting muscarinic and nicotinic skin vasodilatation and sweating.

NEW FINDINGS: What is the central question of this study? It remains to be determined whether type 2 diabetes attenuates muscarinic and nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. What is the main finding and its importance? We show that type 2 diabetes specifically attenuates purinergic cutaneous vasodilatation without influencing muscarinic and nicotinic cutaneous vasodilatation and sweating. Our results provide valuable new information regarding the receptor-specific influence of type 2 diabetes on microvascular and sudomotor function. ABSTRACT: The present study evaluated whether type 2 diabetes (T2D) attenuates muscarinic and/or nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. Cutaneous vascular conductance and sweat rate were evaluated in 12 healthy non-diabetic older adults (Control, 60 ± 8 years) and 13 older adults with T2D (62 ± 10 years) at three intradermal forearm skin sites perfused with the following: (i) methacholine (muscarinic receptor agonist, five doses: 0.0125, 0.25, 5, 100 and 2000 mm); (ii) nicotine (nicotinic receptor agonist, five doses: 1.2, 3.6, 11, 33 and 100 mm); or (iii) ATP (purinergic receptor agonist, five doses: 0.03, 0.3, 3, 30 and 300 mm). Each agonist was administered for 25 min per dose. At the end of the protocol, 50 mm sodium nitroprusside was administered to all skin sites to elicit maximal cutaneous vasodilatation. Cutaneous vascular conductance during methacholine and nicotine administration did not differ between groups (all P > 0.05). In contrast, cutaneous vascular conductance during administration of 30 mm (42 ± 28 versus 63 ± 26% maximum, P ≤ 0.05) and 300 mm ATP (56 ± 24 versus 71 ± 20% maximum, P ≤ 0.05) was attenuated in individuals with T2D in comparison to the Control participants. Furthermore, cutaneous vascular conductance during administration of 50 mm sodium nitroprusside was lower in individuals with T2D relative to Control subjects (P = 0.04). Methacholine- and nicotine-induced sweating was similar between groups (all P > 0.05). Thus, T2D attenuates purinergic cutaneous vasodilatation without affecting muscarinic and nicotinic cutaneous vascular and sweating responses.

Combined treatment of irbesartan and diltiazem ameliorates endothelium dependent vasodilatation in hypertensives.

OBJECTIVE: Endothelial function is of prognostic importance for hypertensives. The aim of this study was to investigate the effects of irbesartan combined with diltiazem on the endothelium-dependent vasodilatation in essential hypertensive (EH) patients in China. METHODS: A total of 150 Chinese hypertensives aged from 40 to 80 years old were assigned into three groups: irbesartan treated(150 mg/d, n = 46), diltiazem treated (90 mg/d, n = 51), and combined therapy group (irbesartan 150 mg/d+ diltiazem 90 mg/d, n = 53). Forty age and gender-matched normotensives without clinical manifestation of cardiovascular diseases served as controls. High-resolution ultrasonography was used to assess flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) in the brachial artery. Left ventricular mass index (LVMI) was calculated. Fibrinogen (Fg) was determined by Clauss and Stago auto analyzer. Blood pressure was measured using mercury sphygmomanometers. RESULTS: FMD and NMD were lower in combined treatment group compared to normotensives before treatment at baseline [FMD(8.39 ± 3.04)% vs. (11.21 ± 3.88)%, NMD (13.96 ± 5.71)% vs. (16.78 ± 6.22)%, p < 0.05]. FMD was improved significantly after the combined therapy [(10.72 ± 3.46)% vs. (8.39 ± 3.04)%, p < 0.05]. No significant difference in NMD was found among three hypertensive groups after therapy. Moreover, FMD increased significantly with the prolongation of treatment. After stratification of age, FMD in younger EH patients under 65 years old was markedly increased after treatment within 1 year, whereas FMD in EH patients over 65 years old showed a significant increase after 3-year therapy. In addition, LVMI was reduced in hypertensives after combined therapy [(99.1 ± 17.9) g/m2 vs. (90.6 ± 16.2) g/m2, p < 0.01]. Logistic analysis showed that age was an important risk factor for FMD. CONCLUSIONS: Combined therapy of irbesartan with diltiazem ameliorated endothelial function.

HIF-1α regulates Cx40-dependent vasodilatation following hemorrhagic shock in rats.

HIF-1α plays an essential role in hemorrhagic shock-induced vasoconstriction. However, the underlying mechanisms remain poorly understood. Here, we studied both the role of HIF-1α in regulating vasodilatation, and the involvement of Cx40 in this process. We found that endothelium-dependent vasodilatation exhibited an overall decline after hemorrhagic shock: at the beginning of shock vasodilatation reactivity significantly decreased, followed by a slight increase from 0.5 h to 2 h after shock. After 2 h vasodilatation dropped again. Throughout this process, protein levels of HIF-1α gradually increased. In the late period of shock, vasodilatation reactivity was enhanced by oligomycin, an HIF-1α inhibitor, suggesting that HIF-1α may promote vasoconstriction. Moreover, in the late period of shock Cx40 levels gradually increased and exhibited a negative correlation with endothelium-dependent vasoconstriction reactivity. Furthermore, Cx40 AODN significantly improved vasoconstriction reactivity and could be regulated by either an HIF-1α inhibitor or an agonist. Together, these data suggest that HIF-1α may inhibit endothelium-dependent vasodilatation reactivity following hemorrhagic shock by up-regulating Cx40, especially in the late period of shock.

Blood transfusions may impair endothelium-dependent vasodilatation during coronary artery bypass surgery.

OBJECTIVE: The hemolytic product free-hemoglobin (fHb) reduces nitric oxide (NO) bioavailability. The present study aims to establish whether administration of different blood transfusions result in increased circulating fHb levels and NO consumption with effects on arterial NO-dependent blood flow in patients undergoing CABG surgery. METHODS: Ninety-five consecutive patients undergoing elective CABG surgery were prospectively divided in four groups based on blood transfusion requirements during surgery: stored blood cells (SBC, n. 21), intraoperative autologous salvaged blood (ASB, n. 25), SBC and ASB (n.22), no transfusion (control, n. 27). Blood samples were collected before and after intervention to analyse plasma levels of fHb and NO consumption. Endothelium-dependent relaxation was assessed in left internal mammary artery (LIMA) rings harvested before chest closure. Peripheral artery tonometry was assessed after intervention. RESULTS: Transfusions with SBC increased plasma fHb (p<0.05). Transfusions of ASB resulted in higher plasma fHb compared to SBC (p<0.01). fHb concentrations directly correlated with NO consumption (r=0.65, p<0.001). Maximal endothelium-dependent relaxation in LIMA was significantly attenuated in SBC and ASB patients compared to control (15.2±3.1% vs 21.1±2.5% vs 43±5.0% respectively; p<0.01). Significant correlations were identified between the aortic pressure wave velocity, plasma fHb concentration and NO consumption (p<0.01). CONCLUSIONS: Intraoperative blood transfusions and particularly autologous salvaged blood impair endothelium-dependent relaxation through NO scavenging by fHb. These findings obtained in vitro and in vivo provide new insights into the adverse relation between blood transfusions and patient outcome.

Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels.

BACKGROUND: Elevated LDL cholesterol is an important risk factor for atherosclerosis. Endothelial dysfunction, an early event in the development of atherosclerosis, is characterized by a reduction in nitric oxide (NO) bioavailability. Arginase has emerged as a key regulator of endothelial function through competition with NO synthase for the common substrate l-arginine. Arginase in endothelial cells is activated by oxidized LDL. The study aim was to investigate the importance of arginase for endothelial dysfunction in patients with familial hypercholesterolaemia (FH). METHODS AND RESULTS: Endothelial function was evaluated in 12 patients with heterozygous FH and 12 age-matched healthy normocholesterolaemic subjects using forearm venous occlusion plethysmography. The evaluations in FH patients occurred when they were on lipid-lowering therapy and 4 weeks after withdrawal of treatment. Endothelium-dependent vasodilatation (EDV) was assessed by intrabrachial artery infusion of serotonin, and endothelium-independent dilatation was assessed by infusion of nitroprusside before and after 120 min administration of the arginase inhibitor N (ω) -hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg min(-1)). In FH patients LDL cholesterol increased from 4.3 ± 0.9 mmol L(-1) at baseline to 7.6 ± 1.9 mmol L(-1) at follow-up (P < 0.001). Arginase inhibition enhanced EDV in FH patients by a similar degree independent of lipid-lowering therapy. The improvement in EDV by arginase inhibition was significantly greater in FH patients than in the control group. CONCLUSION: Arginase inhibition results in greater improvement in endothelial function in patients with FH compared to healthy controls irrespective of their cholesterol levels. Arginase may be a promising therapeutic target for improving endothelial function in patients with hypercholesterolaemia.

Protective effect of growth differentiation factor 11 on aorta in ApoE-/-mice fed with high-fat diet / 中华内分泌代谢杂志

Objective To investigate the effect of growth differentiation factor 11 ( GDF11 ) on aorta in apolipoprotein E-Null( ApoE-/-) mice and its possible mechanisms. Methods Four-week-old healthy male ApoE-/-mice were fed with high-fat diet for 1 week and were then divided into 4 groups:vehicle group(n=10), GDF11 group (n=10),adeno-associated virus-green fluorescent protein group(AAV-GFP group, n=10), and AAV-GDF11 group ( n=10 ) . The mice received intraperitoneal injection with phosphate buffered saline, GDF11 protein, a single injection of purified AAV-GDF11 or AAV-GFP through the tail vein, respectively. After 4 weeks, serum GDF11/8 level and endothelium-dependent vasodilatation were detected. After 12 weeks, serum GDF11/8, interleukin-6 (IL-6), tumor necrosis factor-α( TNF-α), total cholesterol ( TC), triglycerides ( TG), oxidized low density lipoprotein(ox-LDL), and free fatty acids(FFA)levels were measured, the plaque areas in aortic enface and cross sections were measured by oil red O or HE staining, the macrophages/T lymphocytes infiltration in plaques were detected with immunohistochemistry, and the mRNA expressions of IL-6, TNF-α, and IL-10 were determined by real-time PCR. Results Compared with vehicle or AAV-GFP groups, GDF11 and AAV-GDF11 groups presented improved endothelium-dependent vasodilatation, decreased levels of blood inflammatory factors, blood lipid, reduced plaque on face area sections[Vehicle group : GDF11 group:(31. 23 ± 3. 12)% vs (17. 18 ± 2. 17) %;AAV-GFP group : AAV-GDF11 group:(38.01±4.43)% vs(14.54±2.86)%,P<0.05]andcrosssections[Vehiclegroup :GDF11 group:(19. 87 ± 2. 11)% vs (10. 32 ± 1. 47)%;AAV-GFP group : AAV-GDF11 group:(23. 02 ± 2. 76)%vs (9.06±1.63)%, P<0. 05]. There were less macrophages and T lymphocytes infiltration in plaques and lower mRNA expressions of inflammatory factors at aortic wall. Conclusion GDF11 reduces the area of atherosclerotic lesion in ApoE-/-mice, which may be involved in endothelial protection, such as to reduce inflammatory reaction, and to change cellular composition in plaques.

Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention.

Fenofibrate (FF) is widely used to lower blood lipids in clinical practice, but whether its protective effect on endothelium-dependent vasodilatation (EDV) in thoracic aorta is related with endoplasmic reticulum (ER) stress remains unknown. In this study, female Sprauge Dawley rats were divided into standard chow diets (SCD), high-fat diets (HFD) and HFD plus FF treatment group (HFD + FF) randomly. The rats of latter two groups were given HFD feeding for 5 months, then HFD + FF rats were treated with FF (30 mg/kg, once daily) via gavage for another 2 months. The pathological and tensional changes, protein expression of eNOS, and ER stress related genes in thoracic aorta were measured. Then impacts of palmitic acid (PA) and FF on EDV of thoracic aorta from normal female SD rats were observed. Ultimately the expression of ER stress related genes were assessed in primary mouse aortic endothelial cells (MAEC) treated by fenofibric acid (FA) and PA. We found that FF treatment improved serum lipid levels and pathological changes in thoracic aorta, accompanied with decreased ER stress and increased phosphorylation of eNOS. FF pretreatment also improved EDV impaired by different concentrations of PA treatment. The dose- and time-dependent inhibition of cell proliferation by PA were inverted by FA pretreatment. Phosphorylation of eNOS and expression of ER stress related genes were all inverted by FA pretreatment in PA-treated MAEC. Our findings show that fenofibrate recovers damaged EDV by chronic HFD feeding and acute stimulation of PA, this effect is related with decreased ER stress and increased phosphorylation of eNOS.

Obesity impairs vasodilatation and blood flow increase mediated by endothelial nitric oxide: an overview.

Obesity dramatically increases the risk of development of cardiovascular and metabolic diseases. Endothelial dysfunction induced by obesity is an important risk factor that impairs blood flow controls in various organs. Impaired endothelial function occurs early in life in obese children. Obesity-induced endothelial dysfunction is associated with decreased nitric oxide (NO) production due to impaired endothelial NO synthase activity and expression and increased production of superoxide anion and the endogenous NOS inhibitor ADMA, together with increased vasoconstrictor factors, such as endothelin-1 and sympathetic nerve activation. Decreased endothelial progenitor cells are also involved in endothelial cell senescence in obese individuals. Insulin resistance and diabetes mellitus augment obesity-induced endothelial dysfunction. Adipokines liberated from adipose tissues play roles in modulating endothelial function; adiponectin and ghrelin have beneficial effects on endothelial cells. Effects of leptin on endothelial function are controversial. Decreased body weight by physical exercise, dietary interventions, and bariatric surgery are effective measures that reverse endothelial dysfunction; however, the weight control is not only the reason for improving of endothelia function. Pharmacological therapies with ß-adrenoceptor antagonists, resveratolol, anti-obesity agents, nifedipine, and NADPH oxidase inhibitors may also be effective; however, these treatments have to be utilized under the basis of exercise and dietary controls.

Vasodilation reduction and insulin resistance in rats induced by high sucrose, high saturated fatty acid and high unsaturated fatty acid diets / 基础医学与临床

Objective To observe the effects of high sucrose,high saturated fatty acid and high unsaturated fatty acid(diets) on insulin resistance and endothelium-dependent vasodilation function.Methods Adult Wistar rats were divided into normal control(NC) group,high sucrose(HS) group and high saturated fatty acid(HSF) group,high unsaturated fatty acid(HUF) groups.Insulin sensitivity was tested by hyperinsulinemic-euglucemic clamp after 24 weeks.Acetylcholine-induced(or sodium nitroprussideinduced) relaxation of preconstricted isolated renal arteries was measured by Mulvany myograph.Results GIR was obviously lower in experimental groups than that in NC group.GIR was negatively correlated with triglyceride (TG),free fatty acid(FFA).Acetylcholine-induced relaxation was markedly decreased in all experimental groups compared with that in NC group and the maximal response was decreased 37.4% in HSF group,32.7% in HUF group,27.7% in HS group.Acetylcholine-induced relaxation was enhanced by incubation with L-Arg and decreased incubated with L-NNA,MB in all experimental groups.Vasodilation response was negatively correlated with TG,INS and well positively correlated with NO,GIR.There was significantly negative correlation between FFA andNO.Conclusions: The rats fed high sucrose,high saturated fatty acid and high unsaturated fatty acid diets developed insulin resistance with reduced endothelium-dependent vasodilation function.

Improvement of early functional atherosclerotic changes in males with hypercholesterolemia after vitamin E supplementation.

Vitamin E as an antioxidant vitamin reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and may have antiatherosclerotic effects. We tested the hypothesis that six months of 400 mg vitamin E supplementation favourably affects early functional changes in atherosclerotic process in subjects with hypercholesterolemia. The diameter of the brachial artery at rest, after reactive hyperemia (representing endothelium -dependent vasodilatation) and after sublingual glyceryl -trinitrate (representing endothelium - independent vasodilatation), were determined by ultrasonographic method (B mode) before and after the intervention period. After the intervention period the brachial endothelium - dependent vasodilatation increased significantly in the vitamin E group while it did not change in the placebo group. In conclusion, six months of oral vitamin E supplementation results in improvement of the endothelium - dependent vasodilatation in men with hypercholesterolemia.

The relationship between oxidative stress and endothelium-dependent vasodilatation in obese subjects / 中国糖尿病杂志

Objective To evaluate the relationship of the levels of serum oxide and antioxide with endothelium-dependent vasodilatation(EDV) in obese subjects and to explore the effect of oxidative stress on endothelial dysfunction in obese subjects. Methods 20 euglycemic obese males (Ob) and 13 age- matched normal controls (NC) underwent euglycemic hyperinsulinemia clamp study to evaluate the peripheral glucose disposal rate (GDR) in steady-state and brachial artery ultrasound studies to assess the endothelium-dependent vasodilatation (EDV). The serum levels of ROS, MDA, GSH-PX, GSH and free fatty acids (FFAs) were measured. Results The serum ROS, MDA and FFA concentrations were significantly higher in Ob group than in the controls (P

On the endothelium-dependent vasodilation function in insulin-resistant rats / 中华内分泌代谢杂志

Objective To observe the change of endothelium-dependent vasodilatation function and to explore its mechanism in insulin-resistant (IR) rats induced by high fat feed. Methods (1) IR rat model was established by high fat feed for 4 weeks and IR was evaluated by glucose infusion rate (GIR) of euglycemic hyperinsulinemic clamp technique. (2) Acetylcholine (Ach)-dependent vasodilation response and nitric oxide synthase (NOS)-nitric oxide (NO)-cGMP function status were observed in isolated aorta of rats. Results (1) GIR was obviously lower in high fat feed group than that in routine feed group (P