Poly(ADP-ribose) polymerase inhibition prevents homocysteine-induced endothelial dysfunction in the isolated rat aorta

Recent studies have clearly shown that there is a relationship between hyperhomocysteinemia and endothelial dysfunction. However, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on homocysteine (Hcy)-induced endothelial damage has not been investigated. In this study, we investigated whether the loss of endothelial function in rat aortic rings preincubated with Hcy is dependent upon the PARP pathway within the vasculature. Preincubation of rat aortic rings with Hcy (1 mmol/l; 180 min) significantly inhibited endothelium-dependent relaxation in this tissue. This inhibitory effect was significantly reduced in the presence of both superoxide dismutase (100 U ml(-1)) and catalase (100 U ml(-1)) together with Hcy. Similarly, preincubation for 180 min with either N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34; 3 micromol/l) or 3-aminobenzamide (3 mmol/l), structurally different PARP inhibitors, also significantly prevented the development of endothelial dysfunction induced by Hcy. Further incubation of aortic rings with these PARP inhibitors for 60 min after exposure to Hcy for 180 min, at least in part, improved the endothelium-dependent relaxation responses. Thus, our results suggest that intraendothelial PARP activation may be associated with endothelial dysfunction in hyperhomocysteinemic conditions and that inhibition of this pathway may present a novel pharmacological approach to prevent Hcy-induced endothelial damage. Suprisingly, inhibition of the PARP pathway not only prevents the endothelial dysfunction mediated by Hcy, but is also able to rapidly improve it.     

H型高血压患者血管内皮功能变化及与血浆同型半胱氨酸水平的关系

目的 探讨H型高血压患者血管内皮功能变化及与血浆同型半胱氨酸水平(Hcy)的关系.方法 收治的原发性高血压患者120例,根据血浆Hcy水平分为观察组(82例H型高血压患者,Hcy≥10 μmol/L)和对照组(38例单纯原发性高血压患者,Hcy<10 μmol/L),选择同期体检的30例健康志愿者为空白组,检测3组血清一氧化氮(NO)、一氧化氮合成酶(NOS)、肱动脉血管内皮依赖性舒张功能(EDFMD)表达水平,Peaeson直线相关分析法研究原发性高血压患者血浆Hcy表达与血管内皮功能变化的相关性,Logistic 回归分析法分析血管内皮功能指标(NO、NOS、EDFMD)的可能影响因素.结果 高血压患者血浆Hcy较空白组显著较高,观察组H型高血患者Hcy较对照组单纯原发性高血压患者高,差异均有统计学意义(P<0.05);高血压患者血管内皮功能指标NO、NOS、EDFMD较空白组低,观察组上述指标较对照组显著较低,差异均有统计学意义(P<0.05);Peaeson直线相关分析显示高血压血浆hcy表达和血管内皮功能指标均呈显著负相关关系(r=-0.627、-0.608、-0.713,P<0.05);Logistic 回归分析法显示血浆Hcy、收缩压(SBP)、舒张压(DBP)是血管内皮功能损害的影响因素(OR=1.162、1.427、3.584,P<0.05).结论 高血压患者血浆Hcy异常升高和伴有血管内皮功能损害,且在H型高血压患者中表现尤为明显;血浆Hcy过度表达是血管内皮功能指标异常的影响因素,二者表达呈高度负相关.     

Homocysteine impaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signalling

1. Hyperhomocysteinaemia (HHcy) is associated with endothelial dysfunction and has been recognized as a risk factor of cardiovascular disease. The present study aimed to investigate the effect of homocysteine (Hcy) on endothelial function in vivo and in vitro, and the underlying signalling pathways. 2. The HHcy animal model was established by intragastric administration with l ‐methionine in rats. Plasma Hcy and nitric oxide (NO) concentration were measured by fluorescence immunoassay or nitrate reductase method, respectively. Vasorelaxation in response to acetylcholine and sodium nitroprusside were carried out on aortic rings. Human umbilical vein endothelial cells (HUVEC) were treated with indicated concentrations of Hcy in the in vitro experiments. Intracellular NO level and NO concentration in culture medium were assayed. The alterations of possible signalling proteins were detected by western blot analysis. 3. l ‐methionine administration induced a significant increase in plasma Hcy and decrease in plasma NO. Endothelium‐dependent relaxation of aortic rings in response to acetylcholine was impaired in l ‐methionine‐administrated rats. The in vitro study showed that Hcy reduced both intracellular and culture medium NO levels. Furthermore, Hcy decreased phosphorylation of endothelial nitric oxide synthase (eNOS) at serine‐1177 and phosphorylation of Akt at serine‐473. Hcy‐induced dephosphorylation of eNOS at Ser‐1177 was partially reversed by insulin (Akt activator) and GF109203X (PKC inhibitor). Furthermore, Hcy reduced vascular endothelial growth factor (VEGF) expression in a dose‐dependent manner. 4. In conclusion, Hcy impaired endothelial function through compromised VEGF/Akt/endothelial nitric oxide synthase signalling. These findings will be beneficial for further understanding the role of Hcy in cardiovascular disease.     

普罗布考联合叶酸、维生素B12对高同型半胱氨酸血症大鼠内皮功能的影响

【摘要】 目的 探讨普罗布考联合叶酸及维生素B12对高同型半胱氨酸血症(HHcy)大鼠内皮功能的影响。方法 将70只雄性SD大鼠随机分为7组,每组10只:对照(A)组,HHcy模型(B)组,低、中、高剂量普罗布考(C、D、E)组,叶酸+维生素B12(F)组,叶酸+维生素B12+普罗布考(G)组。A组给予普通饲料喂养12周,自第8周末予蒸馏水灌胃4周;其他6组给予2%蛋氨酸饲料12周,自第8周末分别给予蒸馏水、不同剂量普罗布考(340、510、680mg·kg-1·d-1、叶酸+维生素B12、叶酸+维生素B12+普罗布考灌胃4周。分别于实验开始、实验第8、12周末测定大鼠血浆同型半胱氨酸(Hcy)、氧化低密度脂蛋白(OX-LDL)、NO浓度。结果 高蛋氨酸饮食8周末,与A组比较,B组大鼠血浆Hcy、OX-LDL升高,NO水平降低,差异均有统计学意义(P<0.05)。12周末,C、D、E及F组血浆Hcy、OX-LDL水平较B组降低,NO水平升高,与A组差异亦有统计学意义(P<0.05)。G组血浆Hcy、OX-LDL水平较B组下降,NO水平升高,差异有统计学意义(P<0.05),但与A组差异无统计学意义(P>0.05)。血浆Hcy与OX-LDL呈正相关(r=0.823,P<0.05)。结论 普罗布考联合叶酸及维生素B12能更显著地降低Hcy水平,对改善血管内皮功能,减缓动脉粥样硬化具有重要意义。      

Long-lasting partnership between insulin resistance and endothelial dysfunction: role of metabolic memory

Background and Purpose

The persistence of deleterious effects of hyperglycaemia even after glucose normalization is referred to as ‘metabolic memory’. However, similar persistent effects of the metabolic consequences of a high fat diet (HFD) have not been described.

Experimental Approach

Rats were given a normal pellet diet (NPD) or a HFD for 3 months. The animals from the HFD group were then returned to the NPD to observe the long-term effects of insulin resistance. Endothelial dysfunction was assessed by carbachol-mediated vasorelaxation and eNOS phosphorylation.

Key Results

As expected, HFD consumption resulted in insulin resistance and endothelial dysfunction. Phosphorylation of eNOS at S1177 was decreased in HFD rats, compared with that in the NPD group. Rats on 3 months of HFD showed glucose intolerance and impaired insulin sensitivity and were then switched back to NPD (REV group). Levels of cholesterol and triglyceride, and adiposity returned to normal in REV rats. However, endothelium-dependent vascular responses to carbachol which were impaired in HFD rats, continued to be impaired in REV rats. Similarly, decreased eNOS phosphorylation after HFD was not improved after 1 or 6 months of REV.

Conclusions and Implications

Our data indicate that returning to NPD did not improve the insulin sensitivity or the endothelial dysfunction induced by HFD. Although some biochemical parameters responsible for insulin resistance and endothelial dysfunction were normalized, molecular and vascular abnormalities, involving NO, persisted for several months, highlighting the long-lasting effects of metabolic memory.     

Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR-223/NLRP3 axis

OBJECTIVE Atherosclerosis(AS) is an inflammatory disease linked to endothelial dysfunction.Melatonin is reported to possess substantial anti-inflammatory properties, which has proven to be effective in AS. Emerging literature suggests that pyroptosis plays a critical role during AS progression. However, whether pyroptosis contributes to endothelial dysfunction and the underlying molecular mechanisms remained unexploited.This study was designed to investigate the antipyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms. METHODS ApoE-/-mice were fed a high-fat diet to establish an atherosclerotic model, then divided into normal diet(ND) group, normal diet+melatonin(ND+melatonin) group, high fat diet(HFD)group and high fat diet+melatonin(HFD+melatonin) group.After 12 weeks, HE and oil Red O staining were used to detect the formation of atherosclerosis; qRT-RCR and Western blotting were used to detect the expression of NLRP3, ASC, IL-1β, IL-18, GSDMD, NF-κB, miR-223 and MEG3 in aortic endothelium; The luciferase assay was used to detect the binding of mi R-223 to MEG3. Human aortic endothelial cells(HAECs) were pretreated with ox-LDL. After melatonin treatment, qRT-RCR was used to detect the expression of mi R-223 and MEG3. Western blotting was used to detect NLRP3, ASC, c-caspase1,p-caspase1, GSDMD expression. In addition, after overexpressing MEG3 and knocking out mi R-223, the pyroptosis of HAECs was also detected. RESULTS We found intragastric administration of melatonin for 12 weeks markedly reduced the atherosclerotic plaque in aorta.Meanwhile, melatonin also attenuated the expression of pyroptosis-related genes, including NLRP3, ASC,cleaved caspase1, NF-κB/GSDMD, GSDMD N-termini,IL-1β, and IL-18 in aortic endothelium of melatonin-treated animals. Consistent antipyroptotic effects were also observed in ox-LDL-treated human aortic endothelial cells(HAECs). We found that lnc RNA MEG3 enhanced pyroptosis in HAECs. Moreover, MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of mi R-223 and to increase NLRP3 expression and enhance endothelial cel pyroptosis. Furthermore, knockdown of mi R-223 blocked the antipyroptotic actions of melatonin in ox-LDL-treated HAECs. CONCLUSION Our results suggest that melatonin prevents endothelial cell pyroptosis via MEG3/mi R-223/NLRP3 axis in atherosclerosis, and therefore, melatonin replacement might be considered a new strategy for protecting endothelium against pyroptosis, thereby for the treatment of atherosclerosis associated with pyroptosis.     

High-fat diet prevents cardiac hypertrophy and improves contractile function in the hypertensive dahl salt-sensitive rat

1. The role that dietary lipid and plasma fatty acid concentration play in the development of cardiac hypertrophy in response to hypertension is not clear. 2. In the present study, we treated Dahl salt-sensitive rats with either normal chow (NC), normal chow with salt added (NC + salt) or a diet high in long-chain saturated fatty acids with added salt (HFD + salt). Cardiac function was assessed by echocardiography and left ventricular (LV) catheterization. 3. The HFD + salt group had significantly higher plasma free fatty acid concentrations and myocardial triglyceride content compared with the NC + salt group, but did not upregulate the activity of the fatty acid oxidation enzyme medium chain acyl-coenzyme A dehydrogenase. Systolic blood pressure was elevated to a similar extent in the NC + salt and HFD + salt groups compared with the NC group. Although LV mass was increased in the NC + salt group compared with the NC group, LV mass in the HFD + salt group did not differ from that of the NC group and was significantly lower than that in the NC + salt group. 4. There was no evidence of cardiac dysfunction in the NC + salt group compared with the NC group; however, high fat feeding significantly increased LV contractile performance (e.g. increased cardiac output and peak dP/dt). 5. In conclusion, the HFD + salt diet prevented the hypertrophic response to hypertension and improved the contractile performance of the heart. It remains to be determined whether preventing cardiac hypertrophic adaptations would be deleterious to the heart if the hypertensive stress is maintained long term.     

Sesamol inhibits atherogenic LDL-induced endothelial cell senescence in vivo and in vitro

OBJECTIVE Highly electronegative L5 low-density lipoprotein(LDL),an atherogenic LDL,induces endothelial cell(EC)senescence and has been implicated in the progression of atherosclerosis.We examine whether sesamol,a natural organic compound and component of sesame oil,prevents EC senescence induced by electronegative LDL(L5)and to investigate the underlying mechanisms.METHODS Syrian hamsters,which have a LDL profile similar to that of humans,were fed a normal chow diet(control),a high-fat diet(HFD),or a HFD supplemented with the administration of 50 or 100mg·kg-1 sesamol via oral gavage(HFD+sesamol)for 16 weeks(n=10 per group).Among these groups,we compared plasma L5 levels and aortic endothelial senescence in the aortic arch.In vitro,we examined the effects of sesamol on human aortic endothelial cell(HAEC)senescence and signaling pathways induced by L5.RESULTS Hamsters in the HFD group had higher plasma L5 levels than did the HFD+sesamol groups or control group.Betagalactosidase(gal)staining showed that aortic endothelial senescence was markedly increased in the aortic arch of the HFD group but not in that of the HFD+sesamol groups when compared with the control group.In vitro,treatment of HAECs with sesamol(1-3mol·L-1)blocked L5-induced EC senescence in a dose-dependent manner.Sesamol also markedly inhibited the L5-induced phosphorylation of p38 MAPK and p53 activation and increased Mdm2 and phosphorylation of Akt.CONCLUSION The critical findings of this study suggest that sesamol may provide protection against atherosclerosis and the development of cardiovascular disease in humans.     

Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia

The endothelial dysfunction induced by hyperhomocysteinemia can be reversed by 5-methyltetrahydrofolate (5-MTHF) via homocysteine (Hcy) lowering. An additive antioxidant action of 5-MTHF has been suggested to ameliorate endothelial dysfunction through increased nitric oxide production and superoxide radical scavenging, independent of Hcy lowering. The aim of the study was to assess whether 5-MTHF affects the redox state in hyperhomocysteinemia. We examined the effect of 3 months of oral 5-MTHF treatment (15 mg/day) on the redox pattern in 48 hyperhomocysteinemic subjects compared to 24 untreated hyperhomocysteinemic subjects. By analysis of variance with repeated measures in the 72 subjects, 5-MTHF markedly decreased plasma total Hcy (p-tHcy; P = 0.0001) and blood-total glutathione (GSH; b-tGSH; P = 0.002). By multivariate linear regression in the treated subjects, p-tHcy changes from baseline to 3 months (adjusted by baseline p-tHcy levels) correlated only with changes in reduced cysteinylglycine (P = 0.001). The effects of treatment on Hcy lowering and GSH metabolism were greater in medium than in moderate hyperhomocysteinemia. In conclusion, high-dose 5-MTHF treatment for 3 months ensures marked Hcy lowering to normal values even in subjects with high Hcy levels, and should be the treatment of choice in medium hyperhomocysteinemia. Furthermore, 5-MTHF shows a favorable interaction with GSH metabolism.     

Obesity-induced testicular oxidative stress,inflammation and apoptosis: Protective and therapeutic effects of orlistat

Obesity has been reported to induce oxidative stress, inflammation and apoptosis in the testis. The objective of this study was to determine the effects of the anti-obesity drug orlistat, on testicular oxidative stress, inflammation and apoptosis in high-fat diet (HFD)-fed rats. Twenty-four adult male Sprague Dawley rats weighing 250−300 g were randomized into four groups (n = 6/group), namely; normal control (NC), high-fat diet (HFD), HFD plus orlistat (10 mg/kg body weight/day administered concurrently for 12 weeks) (HFD + Opr) and HFD plus orlistat (10 mg/kg body weight/day administered 6 weeks after induction of obesity) (HFD + Ot) groups. Antioxidant enzymes activities were significantly decreased, while mRNA levels of pro-apoptotic markers (p53, Bax/BCl-2, caspase-9, caspase-8 and caspase-3) were significantly increased in the testis of HFD group relative to NC group. Furthermore, the mRNA levels of pro-inflammatory markers (nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis factor alpha and interleukin (IL)-1β increased significantly, while anti-inflammatory marker (IL-10) decreased significantly in the testis of the HFD group relative to NC group. However, in both models of orlistat intervention (protective and treatment models) up-regulated antioxidant enzymes, down-regulated inflammation and apoptosis were observed in the testis of HFD-fed rats. Orlistat ameliorated testicular dysfunction by attenuating oxidative stress, inflammation and apoptosis in HFD-fed rats, suggesting its potential protective and therapeutic effects in the testis compromised by obesity.     

血管内皮功能与Hcy对冠心病型别的影响

目的 分析血管内皮功能与同型半胱氨酸(Hcy)对冠心病型别的影响.方法 选择2014年3月至2016年4月在本院就诊的200例冠状动脉心脏疾病患者,综合分析结果将所有患者分为三组,急性冠脉综合征63例、稳定型心绞痛65例、陈旧性心肌梗死72例.对三组患者高血压、TC(血清总胆固醇)、Hcy以及LDL-C(低密度脂蛋白-胆固醇)等做出对比,分析冠心病病人的症状程度与Hcy和血管内皮功能的关系.结果 急性冠状动脉综合征组的Hcy水平高于其余两组,陈旧性心肌梗死组的Hcy水平高于稳定型心绞痛组,差异有统计学意义(P＜0.05).急性冠状动脉综合征组内皮依赖型舒张率明显低于其余两组,陈旧性心肌梗死组内皮依赖型舒张率明显低于稳定性心绞痛组,差异有统计学意义(P＜0.05).结论 Hcy增高、内皮依赖性舒张率降低会加重冠心病病人的病情.临床上,应对Hcy进行着重检测,及时有效地对患者做出正确的诊断.     

Morin attenuates high-fat diet induced-obesity related vascular endothelial dysfunction in Wistar albino rats

Vascular endothelial dysfunction is caused by dyslipidemia, hypertension, and deficiency of antioxidant systems. In this study, the protective effect of a flavonol, morin was investigated in high-fat diet (HFD)-induced dyslipidemia and vascular endothelium dysfunction. The dose-dependent attenuating effect of morin was tested at doses of 50 and 100 mg/kg/day in an in-vivo model of HFD-induced dyslipidemia using rats whereas vascular endothelial reactivity was assessed in isolated rat aorta using ex-vivo organ bath setup. Morin administration in HFD-induced dyslipidemic rats for three weeks, resulted in a significant decrease in the body weight, LW/BW ratio as compared to rats treated with HFD only where the increase in body weight was observed. Significant reduction in the waist, BMI and lee index was also observed after morin treatment in HFD-induced dyslipidemic rats. In the lipid profile studies, HFD group showed a significant increase in the total cholesterol, triglyceride, LDL, and VLDL levels while HDL levels were decreased significantly, whereas morin treatment reversed all these parameters which were comparable to standard diet (SD) group. In the ex-vivo isolated aorta studies, HFD-induced endothelium dysfunction was observed, whereas it was reversed in the aorta of animals treated with morin at doses of 50 and 100 mg/kg/day, comparable to SD group. Morin treatment produced dose-dependent improvement in lipid profile and vascular endothelium protection, thus rationalizing its medicinal use in dyslipidemia and cardiovascular-related endothelial disorders.     

Pharmacological and toxicological studies of famous Chinese medicine Hua-Feng-Dan

Hua-Feng-Dan(HFD) is a famous traditional Chinese medicine with 370 years of clinical use for stroke paraplegia, epilepsy, facial nerve palsy, moutheye skewed, and other neurodegenerative diseases, and is listed as an intangible cultural heritage of China. HFD contains 15 herbs, minerals and animal products undergoing a special fermentation process to satisfy the "lifting and floating" theory of Chinese medicine. However, the pharmacological basis of HFD remains elusive. We initially discovered its anti-inflammatory effects in rat neuron-glia co-cultures. Further studies found that 35 d administration of HFD at the clinical dose ameliorated the dopaminergic neuron loss and microglia activation in chronic LPS+rotenone rat PD models and in chronic LPS+MPTP mouse PD models, with significant reduction of pro-inflammatory cytokine production and cellular ROS levels. HFD contains heavy metals with increasing concern of its safety.However, removal or reduction of realgar and cinnabar from HFD resulted in abolished or reduced beneficial effects. To further evaluate the safety of HFD, a series of experiments were conducted, including cultured cells,acute and subacute toxicity studies in rodents, and the results clearly demonstrated that realgar(As_4S_4) and cinnabar(Hg S)-containing HFD is much less toxic than environmental arsenic compounds(NaAsO_2 and NaH_2AsO_4)and mercury compounds(HgCl_2 and Me Hg), with much less absorption from the gastrointestinal tract. The gut-brain axis is now implicated in neurodegeneration, and LPS +rotenone or LPS+MPTP induced alterations in gut microbiota, which were significantly ameliorated by HFD. HFD itself also modulates gut microbiome, shedding light on gut-brain axis as one of the possible pharmacological mechanisms. In summary, HFD is effective in preventing dopaminergic neuron loss in both in vivo and in vitro models,and this effect appears to be related to its anti-inflammatory effects and modulation effects on gut microbiota.Realgar and cinnabar are effective ingredients in HFD recipe and the use of Na AsO_2 or HgCl_2 to make risk assessment of realgar(As_4S_4) and cinnabar(HgS) is inappropriate.     

The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins

Neurologists have little concern about the high atherosclerotic risk among epileptics. Recent evidences mount that chronic epilepsy and prolonged use of antiepileptic drugs (AEDs) are associated with multiple risk factors that are critically implicated in pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. This review is concerned with three metabolic alterations, which are attributed as major risk factors for atherosclerosis among epileptics: altered metabolism of a) homocysteine (Hcy), b) lipids and lipoproteins, and c) uric acid. Most conventional AEDs reduce folic acid levels, thereby raising Hcy levels. Hyperhomosysteinemia is recently believed to induce endothelial dysfunction and promote atherosclerosis through complex oxidative and excitatory neurotoxic molecular mechanisms. However, Hcy itself is a convulsing substance with increased seizure recurrence and intractability to antiepileptic medications. AEDs can disturb lipid metabolism with resultant hypercholestrolemia and dyslipidemia, common recognized risks for atherosclerosis. Altered uric acid metabolism is common among epileptics. Uric acid has been implicated in endothelial cell damage and decreased endothelial nitric oxide bioavailability. In the presence of atherosclerotic milieu, uric acid interacts with other substrate toxicities and increased reactive oxygen species, accelerating atherosclerosis. The above information forms the rationale for future routine screening and correction of such metabolic alterations in epileptics. A convincing argument now develops that routine polyvitamin supplementation (folic acid, vitamin B12, vitamin B6, vitamin C, vitamin E, and beta-carotene) becomes increasingly important for women and men receiving AEDs at all ages. The atheroprotective effect of multivitamins is through their antioxidant and anti-inflammatory effects together with their lipid and Hcy lowering effects.     

Vascular hyporeactivity to angiotensin II and noradrenaline in a rabbit model of obesity

This study was conducted to explore the vascular reactivity of angiotensin II and noradrenaline and their relationship with endothelial function in rabbits fed a high-fat diet (HFD). The animals were fed either an HFD or regular chow [control diet (CD)]. After 12 weeks, the rabbits fed the HFD showed higher blood pressure, body weight, and insulin levels. Glucose tolerance was impaired and positively related to blood pressure. An endothelium-independent decrease of the sensitivity to angiotensin II [pD2 endothelium-intact aortic rings (E+) in CD: 8.02 ± 0.07 vs. HFD: 7.60 ± 0.01; pD2 endothelium-removed aortic rings (E-) in CD: 8.16 ± 0.11 vs. HFD: 7.83 ± 0.16] and noradrenaline (pD2 E+ in CD: 6.36 ± 0.06 vs. HFD: 5.29 ± 0.06; pD2 E- in CD: 6.11 ± 0.08 vs. HFD: 5.80 ± 0.08) was found. Noradrenaline desensitized the angiotensin II response (pD2 with noradrenaline pretreatment in E+: 7.03 ± 0.16; in E-: 7.10 ± 0.02), but angiotensin II did not change the noradrenaline response. Acetylcholine maximal relaxation and basal nitric oxide (NO) release were comparable in both diet groups. The efficacy of angiotensin II (Rmax CD: 4604 ± 574 mg vs. HFD: 3251 ± 533 mg) and noradrenaline (Rmax CD: 11,675 ± 804 mg vs. HFD: 7975 ± 960 mg) was reduced in E+. L-N-nitroarginine methyl ester (L-NAME) recovered the efficacy of noradrenaline (Rmax L-NAME: 12,015 ± 317 mg). In contrast, L-NAME had no effect on the angiotensin II response. Noradrenaline enhanced NO levels, but angiotensin II did not. Therefore, NO was associated with hyporeactivity to noradrenaline. The resting potential was more negative in E+, and the endothelium diminished the angiotensin II-induced depolarization. These findings demonstrated that the crosstalk and the endothelium may induce hyporeactivity to angiotensin II and noradrenaline as a mechanism to compensate the increase in the blood pressure in HFD-induced obesity.     

贝那普利对高血压病患者血浆同型半胱氨酸水平和血管内皮功能的影响

目的:研究贝那普利对原发性高血压患者血浆同型半胱氨酸(Hcy)水平和血管内皮功能的影响。方法:77例受试者随机分为治疗组和对照组,对照组给予常规降压治疗,治疗组在此基础上加用贝那普利,观察并比较治疗前、后血浆Hcy水平、内皮依赖性血管舒张功能(FMD)、一氧化氮(NO)浓度及血管性假性血友病因子(v WF)水平等指标的变化。结果:治疗组治疗后与治疗前及对照组治疗后比较Hcy及v WF水平均降低,NO浓度升高,FMD明显升高(P<0·001或P<0·05)。结论:贝那普利降压治疗同时可降低血浆Hcy水平,改善高血压患者的血管内皮功能。     

Ultrastructural examination of rabbit aortic wall following high-fat diet feeding and selenium supplementation: a transmission electron microscopy study

Experiments were carried out to examine the changes occurring in the wall of rabbit aortae following high-fat diet (HFD) feeding as well as HFD + selenium supplementation. Male New Zealand White rabbits were divided into three groups-control, HFD-fed and HFD + Se supplementation-and were treated for three months. The study depicted that levels of serum total cholesterol and triglycerides were markedly increased in the HFD-fed group as compared with control animals. However, in the HFD + Se-fed group, these levels were markedly suppressed vis-à-vis animals fed on HFD only. Development of atherogenic and atheromatic plaques has been shown at the light microscopy level in HFD-fed rabbits, whereas these developments were not visible in the HFD + Se-fed rabbits. Transmission electron microscopy findings indicated altered ultrastructure in the endothelial cells of the intimal layer as well as smooth-muscle cells of the medial layer in HFD-fed animals. However, these findings indicated normal ultrastructure in most of the cells, with little ultrastructural alterations from animals supplemented with Se along with HFD feeding. The study on the whole depicted the ability of Se to inhibit the onset of progression of aortic disease and hence has relevance to its therapeutic potential.     

同型半胱氨酸与勃起功能障碍的相关性研究

目的研究血清同型半胱氨酸（Hcy）与勃起功能障碍（ED）的关系,以及Hcy对其严重程度的影响。方法测定50例ED患者和50例健康男性（对照组）血清Hcy水平,同时记录两组患者年龄、血脂、血糖、前列腺增生（BPH）及国际勃起功能指数5项（IIEF-5评分）。并对其进行Logistic回归分析,分析它们之间的关系。结果 ED组的Hcy水平明显高于对照组,差异具有统计学意义（P=0.013）;ED组的高同型半胱氨酸血症（HHcy）比率（51%）明显高于对照组（12%）,差异具有统计学意义（P=0.020）。ED组高脂血症、高血糖及BPH患者的Hcy与正常血脂、血糖及无BPH患者的Hcy相比差异无统计学意义（P=0.663,P=0.203,P=0.715）。HHcy患者的IIEF-5评分明显低于正常Hcy患者的IIEF-5评分（P=0.017）。多元Logistic回归分析显示HHcy为ED的独立危险因素（OR3.04,95%CI1.39～6.63,P〈0.001）。结论高同型半胱氨酸血症与勃起功能障碍的危险性增加有关,并与其严重程度呈正相关。     

Homocysteine at pathophysiological concentrations enhances binding of dendritic cells to endothelial cells mediated by DC-SIGN

Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis, which is recognized as inflammatory and immune responses. The purpose of this study was to investigate the effect of Hcy on the interaction between dendritic cells (DCs) and endothelial cells (ECs) by upregulating the expression of DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) in cultured DCs. The immunophenotype of Hcy-treated DCs was monitored by flow cytometry. Then, they were coincubated with cultured human umbilical vein endothelial cells, and adhesion of DCs to ECs, and migration of DCs through an endothelial monolayer growing on the insert of a transwell plate, were assessed using a confocal microscope and a multi-detection microplate reader. The expression of DC-SIGN on Hcy-stimulated DCs was assessed by Western blot and immunofluorescence staining. The presence of Hcy did not change the phenotype of immature and mature DCs. Hcy promoted adhesion of DCs to ECs and migration in a concentration-dependent fashion. This effect was inhibited by an anti-DC-SIGN monoclonal antibody. The expression of DC-SIGN on DCs was significantly upregulated by Hcy in a concentration-dependent manner. Taken together, our results show for the first time that Hcy can potentiate the adhesion of DCs to ECs and migration by upregulating the expression of DC-SIGN on DCs, suggesting a novel role of Hcy in the pathogenesis of human vascular disease.