Strain differences in antioxidants in rat models of cardiovascular disease exposed to ozone

Abstract

We examined the hypothesis that antioxidant substances and enzymes in lung, heart and in bronchoalveolar lavage fluid (BALF) are altered in response to O₃ in cardiovascular disease and/or metabolic syndrome (CVD)-prone rat models. CVD strains [spontaneously hypertensive (SH), SH stroke-prone (SHSP), SHHF/Mcc heart failure obese (SHHF), insulin-resistant JCR:LA-cp obese (JCR) and Fawn-Hooded hypertensive (FHH)] were compared with normal strains [Wistar, Sprague–Dawley (SD) and Wistar Kyoto (WKY)]. Total glutathione (GSH?+?GSSG or GSx), reduced ascorbate (AH2), uric acid (UA) and antioxidant enzymes were determined in lung, heart and BALF immediately (0?h) or 20-h post 4-h nose-only exposure to 0.0, 0.25, 0.5 and 1.0?ppm O₃. Basal- and O₃-induced antioxidant substances in tissues varied widely among strains. Wistar rats had a robust O₃-induced increase in GSx and AH2 in the lung. Two CVD strains (JCR and SHHF) had high basal levels of AH2 and GSx in BALF as well as high basal lung UA. Across all strains, high BALF GSx was only observed when high BALF AH2 was present. CVD rats tended to respond less to O₃ than normal. High-basal BALF AH2 levels were associated with decreased O₃ toxicity. In summary, large differences were observed between both normal and CVD rat strains in low-molecular weight antioxidant concentrations in lung, BALF and heart tissue. Wistar (normal) and JCR and SHHF (CVD) rats appeared to stand out as peculiar in terms of basal- or O₃-induced changes. Results elucidate interactions among antioxidants and air pollutants that could enhance understanding of cardiopulmonary disease.     

Whole body plethysmography reveals differential ventilatory responses to ozone in rat models of cardiovascular disease

Abstract

To elucidate key factors of host susceptibility to air pollution, healthy and cardiovascular (CV)-compromised rats were exposed to air or ozone (O₃) at 0.25, 0.5, or 1.0?ppm for 4?h. We hypothesized that rat strains with the least cardiac reserve would be most prone to develop significant health effects. Using flow whole body plethysmography (FWBP), ventilatory responses in healthy 3-month-old male rats [i.e. Wistar–Kyoto (WKY), Wistar (WIS), and Sprague–Dawley (SD) strains] were compared with hypertensive [i.e. spontaneously hypertensive (SH), fawn-hooded-hypertensive (FHH), and SH-stroke-prone (SHSP)] strains and obese [i.e. SH-heart failure-prone (SHHF) and JCR:LA-cp, atherosclerosis-prone (JCR)] strains. SH were slower to acclimate to the FWBP chambers. At 0-h post-air-exposure, SHSP and SHHF exhibited hyperpnea, indicative of cardiopulmonary insufficiency. At 0-h-post-O₃, all but one strain showed significant concentration-dependent decreases in minute volume [MV?=?tidal volume (TV)?×?breathing frequency]. Comparing air with 1.0?ppm responses, MV declined 20–27% in healthy, 21–42% in hypertensive, and 33% in JCR rats, but was unchanged in SHHF rats. Penh increased significantly in all strains, with disproportionate increases in “responder” WKY and FHH strains. By 20?h, most changes had resolved, although Penh remained elevated in WKY, SH, and SHSP. Based on the effective dose estimates (O₃?ppm?×?h?×?MV), the most CV-compromised (SHSP and SHHF) strains received significantly greater O₃ lung deposition (25% and 40%, respectively). Data support epidemiologic associations that individuals with cardiopulmonary insufficiency are at greater risk for urban pollutant exposure due, in part, to enhanced lung deposition and exacerbation of hypoxia and pathophysiologic processes of heart failure.     

Executive Summary: variation in susceptibility to ozone-induced health effects in rodent models of cardiometabolic disease

Abstract

Seven million premature deaths occur annually due to air pollution worldwide, of which ～80% are attributed to exacerbation of cardiovascular disease (CVD), necessitating greater attention to understanding the causes of susceptibility to air pollution in this sector of population. We used rat models of CVD with or without obesity and compared them to healthy strains to examine the risk factors of ozone-induced lung injury and inflammation. We examined functional, biochemical and molecular changes in several organs to evaluate how physiological factors as well as compensatory antioxidant reserves modulate processes by which ozone injury is influenced by underlying disease. In this study, we highlight key findings of this series of reports. We show that underlying cardiopulmonary insufficiency in genetically predisposed rats appears to increase the effective ozone dose; thus dosimetry is one factor contributing to exacerbated ozone effects. We further show that antioxidant reserve in airway lining fluid modulates ozone-induced damage such that strains with the least antioxidant reserve incur the greatest injury. And finally, we show that the inflammatory response to ozone is governed by a cluster of genes involved in regulating cytokine release, trafficking of inflammatory cells and processes related to cellular apoptosis and growth. All such processes are influenced not only by ozone dosimetry and the lung antioxidant milieu but also by the strain-specific genetic factors. In using a comprehensive systems biology research approach, our data reveal key risk factors for – and strategies to reduce risk of – air pollution mortality among those with CVD.     

Variability in ozone-induced pulmonary injury and inflammation in healthy and cardiovascular-compromised rat models

Abstract

The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure dependent on the type and severity of disease. Healthy male 12–14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0?ppm ozone for 4?h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r?=?0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models.     

慢性肾脏病患者血清白细胞介素-2水平与心血管病变相关性分析

目的 探讨慢性肾脏病（CKD）患者血清白细胞介素-2（IL-2）水平及临床意义。方法 按照NKF-K／DOQI标准，采用酶联免疫法对61例CKD患者和正常对照组（25例）测定血清IL-2含量，并检测相关临床指标，分析血清IL-2水平与肾功能、心血管病变及其他临床资料的关系。结果 CKD组患者血清IL-2含量较正常对照组显著升高（P〈0．05），肾功能3、4、5级患者血清IL-2水平较肾功能1、2级显著升高（P均〈0．05）；相关分析显示CKD患者血清IL-2水平与血肌酐呈显著正相关（r=0．412，P〈0．05），与内生肌酐清除率呈显著负相关（r=-0．326，P〈0．05）。CKD心血管病变组血清IL-2水平明显高于无心血管病变组（P〈0．01），高血清IL-2组心血管病变发生率显著高于正常血清IL-2组（P〈0．01）。结论 CKD患者血清IL-2水平升高，与肾功能减退时严重代谢紊乱引起的T细胞活化有关。IL-2升高本身可能作为损伤因子，参与肾功能恶化，并与心血管病变的发生有关。     

心血管疾病患者参与临床决策倾向性的影响因素研究

目的 分析影响心血管疾病患者参与临床决策倾向性的因素.方法 抽取符合入选标准的心血管疾病患者258例,采用问卷调查方法,对患者的就医过程及对其临床决策倾向性的影响进行探讨.问卷调查的具体内容包括：①一般人口学资料;②疾病状况;③患者心理健康状况评估;④患者参与临床决策的意愿.结果 患者平均年龄（64±13）岁;男性占55.8%（144/258）,女性占44.2%（114/258）;88.0%（227/258）的患者可以报销医疗费用;82.2%的患者家庭月收入≥3 000元;89例（34.5%）患者在做临床决策时倾向于＆quot;医生根据医学知识做出决策＆quot;,61例（23.7%）患者在做临床决策时倾向于＆quot;医生在询问患者需求后做出决策＆quot;,94例（36.4%）患者倾向于＆quot;和医生共同做出决策＆quot;,14例（5.4%）患者倾向于＆quot;和医生讨论后自己做出决策＆quot;.无患者依据自己的知识独立做出决策.患者对医生的信任评分：最低7分,最高10分,平均（9.7±0.5）分;文化程度（OR=4.052,95%CI：1.800～9.126）是患者和医生做出共同决策的危险因素,对医生的信任评分（OR=0.071,95%CI：0.016～0.309）是患者和医生做出共同决策的保护因素.结论 心血管疾病患者对医生的信任度很高,患者的临床决策倾向性主要取决于患者对医生的信任程度.     

首发心血管疾病患者血脂水平与心血管疾病发病的相关性分析

目的探讨首发心血管疾病患者血脂水平与心血管疾病发病危险的相关性。方法选取2009年11月至2012年10月浙江省绍兴市人民医院心内科收治的首发心血管疾病患者210例作为观察组,以同期体检健康的志愿者150例作为对照组,采集2组受试者清晨空腹静脉血,检测总胆固醇、三酰甘油、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白（apo）AI及apoB等血脂指标。结果观察组患者总胆固醇、三酰甘油、LDL-C及apoB分别为（6．1±0．3）、（1．9±0．8）、（3．9±1．5）、（1．4±0．7）mmol／L,对照组分别为（4．4±0．6）、（1．1±0．5）、（2．6±0．9）、（0．9±0．3）mmol／L,观察组各项指标均明显高于对照组（t=35．349、10．827、465、8．223,P〈0．05）,而观察组apoA1为（1．5±0．3）mmol／L,低于对照组的（1．9±0．2）mmol／L,差异有统计学意义（t=14．225,P〈0．05）;观察组和对照组受试者体重指数及HDL-C比较,差异均无统计学意义[（26±3）kg／m。比（26±4）kg／m。,（1．4±0．6）mmoL／L比（1．2±0．9）mmol／L]（t=1．748、1．556,均P〉0．05）。观察组210例患者中极高危50例、高危44例、中危64例、低危52例;总胆固醇、三酰甘油、LDL-C及apoB水平与心血管疾病发病的危险分级均呈显著正相关（r=0．786、0．753、0．663、0．900,均P〈0．05）,apoA1与心血管疾病发病的危险分级呈显著负相关（r=-0．691,P〈0．05）。结论首发心血管疾病患者血脂指标的联合检测可作为预测心血管事件发生的重要方法．     

硒蛋白对心血管疾病辅助治疗的临床评价

目的　评价有机硒辅助治疗心血管疾病的临床效果。方法　患者分成两组 ,45例患者在常规治疗的基础上加服有机硒 ,15例患者只进行常规治疗。分别测出两组患者治疗前后的血脂系列和血糖 ,并进行对比分析。结果　 45例患者给予硒蛋白并含有硒化类胡萝卜素制剂辅助治疗后 ,高密度脂蛋白 (HDL )显著提高 ,低密度脂蛋白 (L DL )、甘油三酯 (TG)及总胆固醇 (TC)显著下降 ,并对无糖尿病的心血管病患者血糖影响不大。其效应大大优于对照组。结论　动脉粥样硬化、冠心病等扩张性心肌病的发病原因之一则为低硒 ,有机硒在预防和控制心血管疾病的发展中有一定的作用。     

环磷腺苷葡胺在我院心内科应用的疗效观察

目的:观察环磷腺苷葡胺在我院心内科治疗相关疾病的疗效。方法:应用环磷腺苷葡胺60mg～150mg加入5%葡萄糖注射液中,每日一次静滴。结果:144例住院患者的总有效率大于88%。结论:环磷腺苷葡胺的作用独特,安全范围大,副作用轻微,适应证广泛且疗效确切,可以广泛用于各种心血管疾病。     

Cardiovascular disease in patients with renal disease: the role of statins

ABSTRACT

Objectives: Atherosclerosis is common in patients with chronic kidney disease (CKD), and cardiovascular disease (CVD) represents a major cause of death. The National Kidney Foundation guidelines favour the use of statin therapy for treatment of dyslipidaemia in patients with CKD. Much evidence supports statin therapy for reducing CVD and improving outcomes in the general population, but there is less evidence in patients with CKD. Consequently, prevention of CVD in CKD is based primarily on extrapolation from non-CKD trials. Significantly, in trials specifically designed to investigate patients with CKD, evidence is emerging for improved cardiovascular outcomes with statin therapy. This review describes available data relating to cardiovascular outcomes and the role of statins in patients with CKD, including pre-dialysis, dialysis, and renal transplant patients.

Research design and methods: The PubMed database was searched (1998–present) to ensure comprehensive identification of publications (including randomised clinical trials) relevant to CKD patients, patterns of cardiovascular outcome in such patients and their relationship to lipid profile, and the role of statins for the prevention and treatment of cardiovascular complications.

Results: There are conflicting data on the relationship between dyslipidaemia and cardiovascular outcomes, with one major study of statin therapy (4D – Deutsche Diabetes Dialyse Studie) providing equivocal results. Further studies, including AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events; NCT00240331) in patients receiving haemodialysis, and SHARP (Study of Heart And Renal Protection; NCT00125593) in patients with CKD including those on dialysis, should help to clarify the role of statin therapy in these populations.

Conclusions: More studies are needed to elucidate the role of statins in improving cardiovascular outcomes for CKD patients. It is anticipated that ongoing clinical trials geared towards the optimal prevention and treatment of CVD in patients with CKD will help guide clinicians in the management of CKD.     

系统性红斑狼疮合并心血管疾病的临床研究

目的探讨系统性红斑狼疮合并心血管疾病患者的临床及实验室指标特点及其临床意义。方法回顾性分析144例SLE患者的临床及实验室指标,及其与心血管疾病发生的相关性。结果 144例SLE患者中,60例(41.6%)合并心血管疾病。心脏损害组与心脏未受损害组比较,两组间年龄、病程差异具有统计学意义;且心脏损害组的SLE患者的血红蛋白明显低于心脏未损害组,而C反应蛋白明显高于未损害组(P<0.05)。结论病程长、贫血及CRP增高可能会增加SLE患者合并心血管疾病的发生率,可以作为患者病情判断、预后评估的指标。     

小儿川崎病的临床表现及误诊分析(附30例报告)

目的分析小儿川崎病(KD)的临床表现并探讨误诊原因及防范措施。方法对1996年1月至2007年12月被误诊的30例KD患儿的临床资料进行回顾性分析。结果临床表现呈复杂化、多样化,易被误诊为呼吸系统疾病和消化系统疾病。结论必须提高对KD的认识,注意综合分析复杂多样的临床表现,正确理解诊断标准,动态观察主要临床表现和某些较特异性体征,配合必要的化验和超声心动图检查,尽早确诊,减少冠状动脉损害的发生。     

Caveolae and endothelial dysfunction: filling the caves in cardiovascular disease

Discovery in the early 1990s of caveolin-1, the structural protein responsible for maintaining the Ω shape of caveolae, greatly enhanced investigations to elucidate the role of these little caves in the plasma membrane. Perhaps one of the most important realizations concerning caveolae and caveolin is that these elements play an important functional role in the modulation of cell signal transduction pathways, including those involved in endothelial nitric oxide synthase (eNOS) function. Their role was confirmed by studies with caveolin-1 knockout mice which lack caveolae and display abnormal endothelial function responses. One limitation of these knockout models, however, is that absence of the caveolin protein not only results in the lack of caveolae as a structure but also in the lack of interaction/modulation of enzymes/molecules (e.g. eNOS) to which caveolin binds (whether in- or outside caveolae). In contrast to caveolin knockout models, recent experimental findings suggest that in certain cardiovascular diseases caveolin may dissociate from caveolae to the cytosol, hence decreasing the number of caveolae without a change in the total amount of caveolin. Therefore, as the importance of defining the role of caveolins both in caveolae and in cellular regions is being highlighted, it seems also important at the same time to further define the role of caveolae per se being present in the plasma membrane as a structural entity. The objective of this review is to make an explorative tour on the role of caveolae in vascular endothelial function based on existing literature together with some preliminary experimental findings. Evidence and arguments are put forward that alterations in endothelial caveolae do occur in cardiovascular disease and may contribute to the observed endothelial dysfunction in these conditions.     

Lipid-lowering agents for concurrent cardiovascular and chronic kidney disease

ABSTRACT

Introduction: Cardiovascular disease (CVD) frequently co-exists with chronic kidney disease (CKD). Patients with concomitant CVD and CKD are at very high risk of CVD events.

Areas covered: This narrative review discusses the use of hypolipidaemic drugs in patients with both CVD and CKD. Current guidelines are considered together with the evidence from randomised controlled clinical trials.

Expert opinion: Statins are the first-line lipid-lowering therapy in patients with CVD and CKD. Some statins require dose adjustments based on renal function, whereas atorvastatin does not. Ezetimibe can be prescribed in patients with CVD and CKD, usually combined with a statin. According to current guidelines, statin±ezetimibe therapy should not be initiated, but should be continued, in dialysis-treated CKD patients. Fenofibrate (dose adjusted or contra-indicated according to renal function) and omega 3 fatty acids lower triglyceride levels; whether they also exert cardiorenal benefits in patients with CVD and CKD remains to be established. The use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, cholesterol-reducing nutraceuticals, bempedoic acid and apabetalone in such patients should be investigated. Patients with concomitant CVD and CKD should be treated, in terms of lipid-lowering therapy, early and intensively to minimize their very high risk and possibly, progression of CKD.     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease,AD)是以老年斑和神经纤维缠结为特征的一种进行性、退行性神经系统疾病。AD动物模型的研究可大大促进AD病因、发病机制及药物筛选的研究 ,是深入开展AD研究的必要条件之一。损伤性、自然衰老动物和复合型动物模型能够复制出认知缺损等表现 ,但缺乏AD的特征性病变。SAM P/ 8是相对理想的模型。转基因小鼠是目前研究的热点 ,为在体研究AD的特定发病基因及其代谢产物提供了新的载体。随着AD治疗学由对症治疗转向对因治疗 ,AD模型也应顺应这一发展。     

Left ventricular gene expression profile of healthy and cardiovascular compromised rat models used in air pollution studies

Abstract

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impairment, will reveal underlying disease processes that facilitate understanding of the mechanisms of air pollution susceptibility differences. Left ventricular gene expression was examined using Affymetrix rat 230A-gene arrays in male, age-matched (12–14 weeks old) healthy Wistar Kyoto (WKY) and CV-compromised spontaneously hypertensive (SH), stroke-prone SH (SHSP), obese SH heart failure (SHHF) and obese insulin-resistant (JCR) rats. Principle component analysis separated strains in three clusters: (1) WKY, (2) JCR and (3) SH, SHSP and SHHF. Gene expression pattern in JCR differed from all other CVD strains. Both SHHF and JCR strains presented the most differentially expressed genes from WKY, but generally with opposing directional pattern suggesting that the CVD in these strains arise through different mechanisms. Hierarchical clustering of nuclear factor-kappaB target genes indicated varying degrees of, but similar directional changes, in SH, SHSP and SHHF relative to WKY rats, which may relate to the severity of their CVD. The JCR strain had less pronounced expressions of these genes suggesting milder cardiac disease. No unique expression pattern could be identified for genes implicated in stroke and heart failure in SHSP and SHHF rats, respectively. The data show that the CVD pathophysiological mechanisms differ in models with different genetic backgrounds, and therefore, the mechanisms by which air pollutants affect the cardiopulmonary system are likely to vary.     

口服糖皮质激素与心脑血管疾病风险相关性的临床研究

目的 评价口服糖皮质激素与心脑血管疾病事件发生风险的关系.方法 收集2000～2004年在我院住院的50岁以上患者资料,并随访至2005年,病例组2 035例为确诊的首次冠心痛、心力衰竭、缺血性中风或短暂性脑缺血发作患者,对照组为无前述疾病患者.分析比较口服糖皮质激素与心脑血管事件的风险率(OR).结果 口服糖皮质激素与心脑血管事件明显相关(调整OR1.20,95%CI为1.15～1.25),这种关系在现在应用糖皮质激素者较以往应用者更加明显,且与剂量正相关(调整OR 1.45,95%CI为1.32～1.55).分层分析发现现在应用糖皮质激素与心力衰竭危险增加相关(调整OR 1.58,95%CI为1.41～1.78),且这种关系在合并风湿性关节炎(RA)、慢性阻塞性肺病(COPD)患者中是一致的,分别为(OR 1.45,95%CI为1.09～1.82)、(OR 2.85,95%CI为2.36～3.32).而且,现在应用糖皮质激素与冠心病危险增加相关(调整OR 1.23,95%CI为1.06～1.38).结论 口服糖皮质激素是心力衰竭的危险因素,尤其是现在大剂量服用者.提示临床应注意口服糖皮质激素对心血管痰病的影响,合并其它疾病时更为重要.