中枢氧化应激对心血管疾病的影响

氧化应激为各种原因导致机体内氧化与抗氧化之间平衡失调,活性氧簇(包括:含氧自由基、脂质过氧化物、超氧化物等)产生过多,而使机体处于促氧化状态。超氧化物对于正常细胞功能是必不可少的。现证实,在非吞噬细胞中由NAD(P)H氧化酶催化所产生的超氧化物(及相关的活性氧簇)对机体健康和疾病的发生发展有很大影响。在中枢神经系统中,过多超氧化物引起的氧化应激会影响心血管中枢稳态进而引发各种心血管疾病。尽管现在已知中枢氧化应激与心力衰竭、高血压等多种心血管疾病密切相关,但对其相关机制却报道甚少,现就此做一综述。     

下丘脑室旁核微量注射谷氨酸对心力衰竭大鼠心功能的影响及机制

目的 探讨下丘脑室旁核(PVN)微量注射谷氨酸(Glu)对心力衰竭(HF)大鼠心功能的影响及机制研究。方法 清洁级SD大鼠随机分为假手术(Sham)+人工脑脊液(ACSF)组、HF+ACSF组、HF+Glu组,麻醉状态下用细线结扎左冠状动脉前降支成功建立HF动物模型后下丘脑PVN微量灌注Glu,灌流4 w检测心功能、血浆利钠肽(BNP)、肌酸激酶同工酶(CK-MB)和下丘脑PVN miR-132的表达。结果 HF+Glu组、HF+ACSF组心功能各项指标除心率(HR)外,心肌肥厚指标与Sham+ACSF组相比差异明显(均P<0.05),HF+Glu组HR与HF+ACSF组比较有显著差异(P<0.05)。结论 下丘脑PVN Glu可通过影响下丘脑PVN miR-132的表达加速心功能损害和HF进程。     

下丘脑室旁核氧化应激反应对心力衰竭时肾交感神经活动的影响

目的 探索心力衰竭(HF)时下丘脑室旁核(PVN)氧化应激反应是否能够增强肾交感神经(RSNA)活动,进而促进HF的发生发展.方法 取SD大鼠行冠脉结扎术制作心衰模型,对照组(SHAM)大鼠不结扎冠脉,两天后通过侧脑室插管给予tempol(氧自由基清除剂)或人工脑脊液(VEH).正常饲养4周后,测量各组大鼠血流动力学、RSNA、PVN区域NADPH亚基gp91 phox的表达.结果 HF组大鼠心功能明显低于SHAM组大鼠,RSNA增强、PVN区域NADPH亚基gp91 phox的表达增加.HF大鼠给予tempol治疗后心功能各项指标有所改善,RSNA减弱,PVN区域gp91 phox的表达降低,但达不到SHAM组水平.结论 心衰时PVN区域氧化应激反应增强与RSNA增加有关,降低该区域氧自由基水平可能延缓HF的发生发展过程.     

下丘脑室旁核微量注射精氨酸血管加压素对血管性痴呆大鼠学习记忆的影响

目的探讨下丘脑室旁核(PVN)微量注射精氨酸血管加压素(AVP)对血管性痴呆(VD)大鼠的学习记忆功能的影响及可能机制。方法采用2-VD方法复制VD模型;2 w后PVN注射AVP,采用Morris水迷宫检测大鼠的学习记忆能力,用放射免疫分析测定AVP含量,用荧光分光光度法测去甲肾上腺素(NE)含量。结果 PVN注射AVP可以改善VD大鼠学习记忆能力,海马AVP及NE含量增多。结论 VD的发生可能与下丘脑释放的AVP量减少导致大脑海马内AVP及NE含量减少有关。     

大鼠脑缺血-再灌注后下丘脑室旁核促肾上腺皮质激素的表达

目的 探讨大鼠脑缺血-再灌注后，不同时期中枢下丘脑室旁核促肾上腺皮质激素样阳性免疫物的表达。方法 取雄性Wislar大鼠70只，随机分成对照组（10只）、假手术对照组（30只）及脑缺血-再灌注组（30只）以颈动脉引流法行全脑缺血-再灌注造模，术后分6、24、72h3个时间段取脑，釆用免疫细胞化学技术，用图像分析系统行下丘脑室旁核促肾上腺皮质激素样阳性免疫反应面积、平均吸光度值检测。结果 显微镜下观察示，促肾上腺皮质激素样阳性免疫物呈深棕色，胞核深染，并广泛分布于中枢各脑区，核仁清晰可辨、在丘脑及下丘脑区域有散在分布“串珠”状阳性纤维。图像分析结果显示，假手术对照组、脑缺血-再灌注组大鼠的阳性免疫面积和平均吸光度值呈同步变化：从术后6h开始，假手术对照组、脑缺血-再灌注组大鼠均较正常对照组显着升高，术后24h达高峰（P〈0．05），然后逐渐回落。在3个不同时间段，3组间差异均有显着意义（P〈0．05），术后6及24h为：脑缺血-再灌注组，假手术对照组，正常对照组；术后72h为：假手术对照组〉正常对照组〉脑缺血-再灌注组。结论 在脑缺血-再灌注不同时间段，下丘脑室旁核神经元促肾上腺皮质激素样阳性免疫物表达呈现明显的时间规律；促肾上腺皮质激素可能在神经元功能调控，中枢内环境控制及脑缺血-再灌注损伤过程中发挥着重要作用。     

下丘脑室旁核miR-132对心力衰竭大鼠外周交感神经兴奋性的影响

目的 观察下丘脑室旁核(PVN)灌注miR-132特异抑制剂对心力衰竭(HF)大鼠外周交感神经兴奋性、下丘脑谷氨酸(Glu)含量及心脏功能的影响。方法 雄性SD大鼠随机分为正常对照(Ctrl)+人工脑脊液(ACSF)组、HF+ACSF组、HF+miR-132抑制剂组。结扎心脏左冠状动脉前降支制造HF动物模型,HF+miR-132抑制剂组侧脑室插管向PVN内灌注miR-132特异抑制剂,Ctrl+ACSF组和HF+ACSF组灌注等量ACSF,灌注后4 w进行心脏功能指标检测;镜下观察心肌结构变化;检测肾脏交感神经放电(RSNA)、HF标志物脑钠肽(BNP)和外周交感神经兴奋标志物去甲肾上腺素(NE)在血浆中的含量;检测Glu在下丘脑PVN的含量。结果 与Ctrl+ACSF组相比,HF+ACSF组心功能指标恶化、外周交感神经兴奋性增强、下丘脑PVN Glu含量升高、心肌组织病理改变明显(P<0.05);HF+miR-132抑制剂组与HF+ACSF组比较,HF大鼠上述检测指标均显著改善(P<0.05)。结论 下丘脑PVN miR-132可影响HF大鼠的外周交感神经兴奋性和心脏功能...     

中枢神经系统对心力衰竭的作用

心力衰竭为多数心血管疾病的最终归宿,其发病率呈上升趋势。中枢和外周交感神经系统的过度激活、活性氧、炎性因子的蓄积以及酶和离子通道的病理改变与心力衰竭发生发展密切相关。该文着重论述以室旁核为代表的中枢神经系统在慢性心力衰竭发生发展中作用。     

依普利酮对心力衰竭大鼠下丘脑室旁核内炎性因子的抑制作用

目的探讨依普利酮对心力衰竭大鼠下丘脑室旁核(PVN)内炎性因子的抑制作用。方法 SD大鼠结扎冠状动脉前降支造成急性心肌梗死后心力衰竭模型。其中一组给予核因子(NF)-κB拮抗剂PDTC灌胃(0.2 g/kg);另一组给予依普利酮(30 mg/kg);第3组以相同体积的蒸馏水灌胃作为对照。6 w后测量心脏功能,采集PVN和外周血标本,检测炎性细胞因子等指标。结果依普利酮与PDTC干预的大鼠心功能较心力衰竭组明显改善。心力衰竭组神经元活性增强,PDTC和依普利酮可显著降低PVN内神经元活性。对照组PVN内肿瘤坏死因子(TNF)-α、促肾上腺皮质激素释放激素(CRH)、NF-κB表达明显升高(P0.05)。依普利酮与PDTC干预的大鼠与心力衰竭组大鼠相比这些指标表达减少(P0.05)。心力衰竭组外周血醛固酮(ALD)、去甲肾上腺素(NE)、TNF-α水平升高。依普利酮、PDTC治疗组ALD、NE、TNF-α水平较对照组明显降低。结论依普利酮可以改善大鼠心功能,可能与其抑制PVN内NF-κB表达,进而抑制PVN内炎性反应有关。     

艾司洛尔联合丹参多酚酸盐对老年冠心病心绞痛患者心功能、血流动力学及氧化应激指标的影响

目的探讨艾司洛尔联合丹参多酚酸盐治疗老年冠心病心绞痛患者的临床疗效及对氧化应激的影响。方法108例老年冠心病心绞痛患者,根据治疗方式的不同分为对照组、观察组各54例。对照组给予艾司洛尔治疗,观察组给予艾司洛尔联合丹参多酚酸盐治疗,比较两组治疗疗效、不良反应发生情况及治疗前后的心功能、血液流变学、氧化应激指标水平变化。结果观察组的治疗总有效率显著高于对照组(P<0.05);治疗后两组左室收缩末期容积(LVESV)、左室舒张末期容积(LVEDV)较治疗前明显降低,而左室血压血分数(LVEF)明显升高(P<0.05),且观察组LVESV、LVEDV水平低于对照组,LVEF值高于对照组(P<0.05);治疗后两组血浆黏度、全血黏度低切、全血黏度高切、纤维蛋白原水平均显著低于治疗前(P<0.05),且观察组各血液流变学指标水平显著低于对照组(P<0.05);治疗后两组超氧化物歧化酶(SOD)水平均显著高于治疗前,丙二醛(MDA)水平均显著低于治疗前(P<0.05),且观察组SOD明显高于对照组,MDA明显低于对照组(P<0.05);两组不良反应总发生率比较无明显差异(P>0.05)。结论对老年冠心病心绞痛患者应用艾司洛尔联合丹参多酚酸盐治疗能够取得较好的临床疗效,对患者的心功能有明显的改善效果,同时能够降低血液黏稠度及氧化应激程度,且安全可靠。     

通心络治疗冠心病心绞痛对氧化应激及炎性因子的影响

目的探讨通心络联合曲美他嗪治疗稳定型心绞痛的临床效果及对患者氧化应激及炎性因子水平的影响。方法选取我院收治的120例稳定型心绞痛患者,采用随机数字表法分为观察组和对照组各60例,观察组采用基础治疗+通心络+曲美他嗪治疗,对照组采用基础治疗+曲美他嗪治疗;对比两组患者治疗后的心绞痛发作次数、心绞痛持续时间、每周硝酸甘油使用量、治疗前后的血清丙二醛(MDA)、超氧化物歧化酶(SOD)、一氧化氮(NO)、肿瘤坏死因子-α(TNF-α)、超敏C反应蛋白(hs-CRP)、白细胞介素-6(IL-6)的变化。结果治疗后,观察组患者的心绞痛发作次数、心绞痛持续时间、每周硝酸甘油使用量均显著低于对照组(t=-3. 72～-9. 29,P 0. 05);观察组患者的临床疗效优于对照组,差异具有统计学意义(P 0. 05);治疗后,观察组患者的血清MDA、NO、TNF-α、hs-CRP、IL-6水平均低于对照组,差异具有统计学意义(t=-1. 07～-5. 28,P 0. 05),观察组的SOD水平高于对照组,差异具有统计学意义(P 0. 05)。结论通心络联合曲美他嗪治疗冠心病稳定型心绞痛效果肯定,能有效地改善患者氧化应激水平及炎性反应程度。     

丹参多酚酸盐对猪急性心肌梗死后氧化应激指标和脑钠肽的影响

目的 观察丹参多酚酸盐对猪急性心肌梗死后氧化应激和脑钠肤(BNP)的影响.方法 苏中幼猪21只,随机分为高剂量组、低剂量组和对照组,3组均经开胸结扎冠状动脉前降支制作心肌梗死模型,造模成功后,高剂量组予250 mL 5%葡萄糖加入400 mg丹参多酚酸盐;低剂量组予250 mL 5%葡萄糖加入200 mg丹参多酚酸盐,结扎后当天开始经静脉途径静脉输注.对照组经静脉途径应用250mL静脉输注,均为1次/天,疗程7d.测定不同时间血浆中超氧化物歧化酶(SOD)、谷胱甘肤过氧化物酶(GSH-Px)及BNP的水平;造模后4周行门控心肌显像评价心功能.结果 对照组抗氧化酶活性下降,表现为血浆中SOD和GSH-Px活力下降(P<0.05).使用丹参多酚酸盐治疗后,抗氧化酶(SOD和GSH-Px)活力升高(P<0.05).两治疗组心功能高于对照组,在1个月实验终点,血浆中BNP下降,与对照组比较差异有统计学意义(P<0.05),术后1个月的BNP与左室射血分数(LVEF)呈负相关(r=0.56,P<0.05).结论 经静脉途径维持应用丹参多酚酸盐能够降低血浆BNP水平,具有氧自由基清除活性,可阻断心肌梗死后的氧化应激状态,促进梗死心脏心功能改善,对心肌梗死后的心脏发挥保护作用.     

Effect of Low-Dose Aspirin on the Markers of Oxidative Stress

Summary. The present study estimates effects of low-dose enteric coated aspirin (ECA) on oxidative stress (OS) markers in a group of middle-aged men (mean age 51.2 ± 6.9 years) free of pre-existing ischemic heart disease.Methods. Serum products of lipid peroxidation, and measures of antioxidative status were detected in 25 healthy men in baseline and after two-week treatment period.Results. In respect to serum products of lipid peroxidation and markers of antioxidant status, no statistically significant differences between the pre- and after-treatment data were observed for any measures, with the exception of values of serum antioxidative capacity (39.0 ± 2.5 and 42 ± 4.6, respectively).Conclusions. Administration of ECA does not initiate the OS in blood and improves the general antioxidative potency of blood. This may imply towards certain antiatherogenic influence of low-dose ECA, exhibited even with a short-term treatment period. Regarding OS markers, a variety of individual responses observed in the selected subgroups should be investigated and possibly taken into account while treatment with ECA is initiated for primary prevention of cerebrovascular events.     

Association between Oxidative Stress Assessed by Urinary 8-Hydroxydeoxyguanosine and the Cardiac Function in Hypertensive Patients without Overt Heart Disease

Although increased oxidative stress is known to be associated with worsened cardiac function in chronic heart failure, consensus is still lacking regarding the association between oxidative stress and cardiac function in hypertensive patients without overt heart disease. This study aimed to evaluate the association between oxidative stress assessed by urinary 8-hydroxydeoxyguanosine (8-OHdG) and cardiac function in hypertensive patients without overt heart disease. We enrolled a total of 80 hypertensive patients (70 ± 11 y) who had been taking antihypertensive medications for at least 1 year. Urinary 8-OHdG levels were measured by an immunochromatographic assay (ICR-001, Selista Inc., Tokyo, Japan). Echocardiography was performed to assess the left ventricular (LV) diastolic function by measuring early diastolic mitral annular velocity (e′) and the ratio of early transmitral flow velocity (E) to e′ (E/e′). Urinary 8-OHdG was correlated with E/e′ (r = 0.346, P = .002), e′ (r = ?0.310, P = .005), and HbA1c (r = 0.276, P = .013). Multiple linear regression analysis revealed that only e′ (β = ?0.343, P = .004) was an independent determinant of urinary 8-OHdG. In conclusion, decreased e′ is independently associated with elevated urinary 8-OHdG, a marker of oxidative stress, in hypertensive patients. Therefore, an elevated urinary 8-OHdG level may be useful in detecting subclinical LV diastolic dysfunction in hypertensive patients without overt heart disease.     

Menadione-Induced Oxidative Stress in Bovine Heart Microvascular Endothelial Cellsa

Objective: Oxidative stress from increased production of reactive oxygen species or decreased efficiency of inhibitory and scavenger systems may contribute to vascular injury. In this study, we developed an in vitro model of vascular injury by menadione-induced oxidative stress in bovine heart microvascular endothelial cells. Methods: Oxidative stress was induced by exposure to menadione. Superoxide, hydrogen peroxide and hydroxyl radical formation was measured by superoxide dismutase-inhibitable cytochrome c reduction, the dichlorofluorescin technique and the salicylate method, respectively. Electron paramagnetic-spin resonance spectroscopy employing 5–5′-dimethyl-1-pyrroline-N-oxide for superoxide trapping was used. Endothelial cell cytotoxicity was assessed by lactate dehydrogenase release. Results: Superoxide and hydroxyl radical were produced in a time- and concentration-dependent fashion. Fluorescence in the presence of dichlorofluorescin confirmed hydrogen peroxide formation. Endothelial cell cytotoxicity became evident after 5 h of menadione treatment at concentrations of 100 μM. 3-Aminobenzamide, a poly(ADP-ribose)polymerase inhibitor, and dimethylthiourea, a hydrogen peroxide and hydroxyl radical scavenger, decreased menadione cytotoxicity, whereas deferoxamine, an inhibitor of hydroxyl radical formation, did not. Conclusions: The results suggest that menadione toxicity is mediated by poly(ADP-ribose)polymerase activation via hydrogen peroxide formation and that menadione-treated bovine heart microvessel endothelial cells provide a suitable in vitro model to study oxidative stress in endothelial cells.     

Dexrazoxane Prevents Myocardial Ischemia/Reperfusion-Induced Oxidative Stress in the Rat Heart

Introduction Dexrazoxane (Dex), used clinically to protect against anthracycline-induced cardiotoxicity, possesses iron-chelating properties. The present study was designed to examine whether Dex could inhibit the ischemia/reperfusion (I/R) induced damage to the rat heart. Materials and methods Isolated perfused rat hearts were exposed to global ischemia (37°C) and 60 min reperfusion. Dex was perfused for 10 min prior to the ischemia, or administered intraperitoneally (150 mg) 30 min prior to anesthesia of the rats. I/R caused a significant hemodynamic function decline in control hearts during the reperfusion (e.g., the work index LVDP X HR declined to 42.7 ± 10%). Dex (200 μM) applied during the preischemia significantly increased the hemodynamic recovery following reperfusion (LVDP X HR recovered to 55.7 ± 8.8%, p < 0.05 vs. control). Intraperitoneal Dex, too, significantly increased the hemodynamic recovery of the reperfused hearts. I/R caused an increase in oxidation of cytosolic proteins, while Dex decreased this oxidation. Discussion The decrease in proteins carbonylation and correlative hemodynamic improvement suggests that Dex decreases I/R free radical formation and reperfusion injury. Eyal Ramu and Amit Korach contributed equally to this study.     

炎症、氧化应激与心房颤动

许多证据表明心房颤动中存在炎症和氧化应激,炎症和氧化应激可导致心房重构,包括电重构和结构重构,提示炎症和氧化应激可能在心房颤动的发生和维持中起着一定作用。抗炎和抗氧化治疗可减少心房颤动的发生和复发,这为干预心房颤动的发生和复发提供了新思路。     

Effect of Iron Supplementation on Oxidative Stress and Intestinal Inflammation in Rats with Acute Colitis

In this study, we investigated the effect of intraperitoneal iron dextran (100mg/100 g body weight) on oxidative stress and intestinal inflammation in rats with acute colitis induced by 5% dextran sulfate sodium. In both colitis and healthy animals, disease activity index, crypt and inflammatory scores, colon length, plasma and colonic lipid peroxides, and plasma vitamins E, C, and retinol were assessed. The results showed that iron-supplemented groups had moderate iron deposition in the colonic submucosa and lamina propria. In the colitis group supplemented with iron, colon length was significantly shorter; disease activity index, crypt, and inflammatory scores and colonic lipid peroxides were significantly higher; and plasma -tocopherol was significantly lower compared to the colitis group without iron supplementation. There was no intestinal inflammation and no significant increase in colonic lipid peroxides in healthy rats supplemented with iron. In conclusion, iron injection resulted in an increased oxidative stress and intestinal inflammation in rats with colitis but not in healthy rats.     

In Vitro Effect of Homocysteine on Some Parameters of Oxidative Stress in Rat Hippocampus

Homocystinuria is an inherited metabolic disease characterized biochemically by increased blood and brain levels of homocysteine caused by severe deficiency of cystathionine -synthase activity. Affected patients present mental retardation, seizures, and atherosclerosis. Oxidative stress plays an important role in the pathogenesis of many neurodegenerative and vascular diseases, such Alzheimer's disease, stroke, and atherosclerosis. However, the mechanisms underlying the neurological damage characteristic of homocystinuria are still poorly understood. To evaluate the involvement of oxidative stress on the neurological dysfunction present in homocystinuria, we measured thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and total radical-trapping antioxidant potential (TRAP) and antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase) in rat hippocampus in the absence (controls) or in the presence of homocysteine (10–500 M) in vitro. We demonstrated that homocysteine significantly increases TBARS and decreases TRAP, both in a dose-dependent manner, but did not change antioxidant enzymes. Our results suggest that oxidative stress is involved in the neurological dysfunction of homocystinuria. However, further studies are necessary to confirm and extend our findings to the human condition and also to determine whether antioxidant therapy may be of benefit to these patients.