Genetic Specificity of Stress-Induced Anemia in Rats

There is a genetic difference in rat hemoglobin (Hb) β-chain structure, with alternate alleles, A and B, at a single locus. This study was designed to find out whether marrow sensitivity due to γ exposure and experimentally induced anemia in age-matched adult rats is entirely strain specific or is a combination of both strain and Hb genotype. Eight strains of inbred and outbred rats comprising AA and BB types were examined. The data indicate that there is a relationship between marrow sensitivity and Hb genotypes in response to erythropoietic stress caused by three techniques.     

A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

A genomewide screen for quantitative-trait loci (QTLs) that underlie asthma was performed on 533 Chinese families with asthma, by the unified Haseman-Elston method. Nine asthma-related phenotypes were studied, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), airway responsiveness as indicated by methacholine (MTCH)-challenge test, serum total immunoglobulin E (TIgE), serum-specific immunoglobulin E, eosinophil count in peripheral blood, and skin-prick tests with three different allergens (cockroach, Dermatophagoides pteronyssinus, and D. farinae). Our study showed significant linkage between airway responsiveness to MTCH and D2S1780 on chromosome 2 (P<.00002) and provided suggestive evidence (P<.002) for six additional possible QTLs: D10S1435 and D22S685, for FEV1; D16S412, for FVC; D19S433, for airway responsiveness to MTCH; D1S518, for TIgE; and D4S1647, for skin reactivity to cockroach. No significant or suggestive evidence of linkage for the other four traits was found.     

HMGB1 Promotes the Development of Pulmonary Arterial Hypertension in Rats

Rationale

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.

Objectives

To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.

Methods

Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.

Results

HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.

Conclusions

Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.     

Genetic Polymorphism of Experimentally Produced Forms of Arterial Hypertension

Russian Journal of Genetics - The paper analyzes the distribution of polymorphic loci in rats of different hypertensive strains. When analyzing the transcribed loci of ISIAH rats and the...     

Aspirin Attenuates Pulmonary Arterial Hypertension in Rats by Reducing Plasma 5-Hydroxytryptamine Levels

Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary pressure, right ventricular failure, and death. The typical pathological changes include medial hypertrophy, intimal fibrosis and in situ thrombosis. Serotonin (5-HT) and other factors contribute to the development of pathologic lesions. Aspirin (ASA), a platelet aggregation inhibitor, inhibits 5-HT release from platelets. The aim of this study was to determine the efficacy of ASA in preventing or attenuating PAH. Sprague–Dawley rats injected with monocrotaline (MCT) developed severe PAH within 31 days. One hundred forty rats were randomized to receive either vehicle or ASA (0.5, 1, 2, or 4 mg/kg/day). The pre-ASA group was treated with ASA (1 mg/kg/day) for 30 days before the MCT injection. Thirty-one days after the injection (day 61 for the pre-ASA group), pulmonary arterial pressure (PAP), right ventricular hypertrophy and pulmonary arteriole thickness were measured. Plasma 5-HT was measured by high-performance liquid chromatography. Aspirin suppressed PAH and increased the survival rate compared with the control group (84 vs. 60%, P < 0.05). Aspirin treatment also reduced right ventricular hypertrophy and pulmonary arteriole proliferation in ASA-treated PAH model. In addition, plasma 5-HT was decreased in our ASA-treated PAH model. The degree of 5-HT reduction was associated with systolic PAP, right ventricular hypertrophy and wall thickness of pulmonary arterioles in rats. These results showed that ASA treatment effectively attenuated MCT-induced pulmonary hypertension, right ventricular hypertrophy, and occlusion of the pulmonary arteries. The effects of ASA was associated with a reduction of 5-HT.     

Aldosterone Biosynthesis: Genetic Control and Contribution to the Development of Arterial Hypertension

Russian Journal of Genetics - Data on the contribution of gene polymorphism of proteins and enzymes of aldosterone metabolism to arterial hypertension are considered. On the basis of the analysis...     

他达那非治疗肺动脉高压进展

肺动脉高压是一类以小肺动脉血管重构为特征的恶性肺血管疾病,肺血管阻力进行性升高最终导致右心衰竭死亡。肺动脉高压的药物治疗主要针对前列环素、内皮素、一氧化氮三个靶点。他达那非(Tadalafil)是一种口服、长效、选择性5-型磷酸二酯酶抑制剂,增加环磷酸鸟苷(cGMP)浓度,通过一氧化氮途径起到治疗作用。PHIRST临床试验证实肺动脉高压患者每日一次口服他达那非40mg,能够提高6分钟步行距离,减少临床恶化。本文就他达那非治疗肺动脉高压研究新进展作一综述。     

Genetic Loci for Retinal Arteriolar Microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10⁻⁸. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10⁻¹² in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.     

A Genetic Map of Quantitative Trait Loci for Body Weight in the Mouse

The genetic basis of body weight in the mouse was investigated by measuring frequency changes of microsatellite marker alleles in lines divergently selected for body weight from a base population of a cross between two inbred strains. In several regions of the genome, sharp peaks of frequency change at linked markers were detected, which suggested the presence of single genes of moderate effect, although in several other regions, significant frequency changes occurred over large portions of chromosomes. A method based on maximum likelihood was used to infer effects and map positions of quantitative trait loci (QTLs) based on genotype frequencies at one or more marker loci. Eleven QTLs with effects in the range 0.17-0.28 phenotypic standard deviations were detected; but under an additive model, these did not fully account for the observed selection response. Tests for the presence of more than one QTL in regions where there were large changes of marker allele frequency were mostly inconclusive.     

肾上腺皮质激素在应激性高血压发病中的中枢机制

本工作观察到应激性高血压大鼠发病过程中伴随着出现血浆儿茶酚胺,皮质酮以及血糖,血脂的平行升高,肾上腺皮质激素微量注射至延髓头端腹外侧区可引起升压,加快心率及增强防御性升压反应,该作用可能是应激性高血压发病机制的重要环节之一,其机制可能通过对该区神经元的快速膜效应而实现,并与该区胆碱能系统活动的异常增强和钙通道的激活有关。     

胁迫诱导型启动子在植物抗逆基因工程中的应用

在抗逆基因工程中,大多采用的是组成型表达启动子,组成型表达启动子驱动外源抗逆基因表达虽然可以提高转基因植物的抗逆性,但会导致转基因植株生长迟缓或不育;而胁迫诱导型启动子则可提高转基因植物的抗逆性,不影响其正常生长发育,所以,胁迫诱导型启动子已逐渐用于植物抗逆基因工程。本文介绍不同胁迫诱导型启动子在植物抗逆基因工程中的应用。     

聚焦治疗肺动脉高压的靶向药物

肺动脉高压(PAH)是一种以血管收缩和重构所致的肺血管阻力升高为病理生理学特征的临床综合征,其呈进行性发展,最终可 导致右心衰竭甚至死亡,预后差。随着对 PAH 病理生理学机制的深入研究,该病所涉不同信号通路的关键位点逐渐被认识,相应的靶向 药物也不断涌现,它们的应用明显改善了PAH患者的生活质量和预后。综述针对PAH 发生发展过程中所涉的3条主要通路:前列环素通路、 内皮素通路和一氧化氮-鸟苷酸环化酶-环磷酸鸟苷通路以及其他靶点(如酪氨酸激酶受体和 Rho 激酶等)而开发的靶向药物研究进展。     

Arterial Stiffening Provides Sufficient Explanation for Primary Hypertension

Hypertension is one of the most common age-related chronic disorders, and by predisposing individuals for heart failure, stroke, and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure arise as emergent properties of the integrated system. The results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function.     

不同剂量野百合碱诱导大鼠肺动脉高压模型的实验研究

目的:肺动脉高压患者的预后非常差并且目前对肺动脉高压的治疗缺乏有效的方法.因此,对肺动脉高压的研究十分迫切,而建立稳定、操作简便、稳定的肺动脉高压模型是研究肺动脉高压的基础.本实验的目的就是采用不同剂量野百合碱(monocrotaline,MCT)诱导建立SD大鼠肺动脉高压模型,探讨肺动脉高压模型的制作方法及其稳定性.方法:清洁级SD雄性大鼠75只,随机分为C组、M1、M2、M3和M4组,每组各15只.其中M1～M4组大鼠分别一次性腹腔注射MCT 30、40、50和60 mg/kg,诱导制作肺动脉高压动物模型;C组为对照组,给予相同剂量溶剂腹腔注射.腹腔注射4周后比较各组大鼠的生存率、检测平均肺动脉压力(mPAP),肺动脉收缩压(PASP),右心肥大指数(RVHI),并取肺组织行苏木素-伊红染色,观察肺的病理改变,采用肺小动脉形态计量学指标综合判断肺动脉高压模型的稳定性.结果:C组无死亡,M1～M4组大鼠的生存率分别为87％,87％,67％,40％.M1～M4各组SD大鼠平均肺动脉压、肺动脉收缩压、右心肥大指数依次增大(P＜0.05),肺小动脉形态计量学指标检测显示肺血管中膜厚度百分比依次增大(P＜0.05),而M3与M4组各测量结果无明显差异.结论:腹腔注射50 mg/kg、60 mg/kg剂量野百合碱均可引起大鼠肺动脉压力升高和肺血管重构,均可诱导稳定的肺动脉高压模型,而50 mg/kg剂量有更高的生存率.所以50mg/kg剂量野百合碱腹腔注射是成功诱导大鼠肺动脉高压模型的合适剂量.     

A Screen for Genetic Loci Required for Body-Wall Muscle Development during Embryogenesis in Caenorhabditis Elegans

We have used available chromosomal deficiencies to screen for genetic loci whose zygotic expression is required for formation of body-wall muscle cells during embryogenesis in Caenorhabditis elegans. To test for muscle cell differentiation we have assayed for both contractile function and the expression of muscle-specific structural proteins. Monoclonal antibodies directed against two myosin heavy chain isoforms, the products of the unc-54 and myo-3 genes, were used to detect body-wall muscle differentiation. We have screened 77 deficiencies, covering approximately 72% of the genome. Deficiency homozygotes in most cases stain with antibodies to the body-wall muscle myosins and in many cases muscle contractile function is observed. We have identified two regions showing distinct defects in myosin heavy chain gene expression. Embryos homozygous for deficiencies removing the left tip of chromosome V fail to accumulate the myo-3 and unc-54 products, but express antigens characteristic of hypodermal, pharyngeal and neural development. Embryos lacking a large region on chromosome III accumulate the unc-54 product but not the myo-3 product. We conclude that there exist only a small number of loci whose zygotic expression is uniquely required for adoption of a muscle cell fate.     

Psychological Stress-Induced Lower Serum Zinc and Zinc Redistribution in Rats

In humans, long-term exposure to uncontrollable and unpredictable life stressors is a major precipitant in the development of depressive disorders. There are strong evidences that depression is accompanied by lower serum zinc. The aim of present study is to assess the effects of repeated psychological stress (PS) on the zinc metabolism in rat. The rats were divided into control group and PS group which were subdivided into three subgroups: 7-day group, 14-day group, and recovery group (ten rats in each subgroup). PS model was created by a communication box which contains room A and room B. Rats in room A were only exposed to the responses of rats which were randomly given electrical shock for 30 min in room B. PS was given to rats for 30 min every morning for 14 days. The serum corticosterone (CORT), zinc in serum and tissues, and zinc apparent absorption after PS exposure were investigated. The results showed that the serum CORT increased and serum zinc decreased after 7 and 14 days of PS treatment. The zinc concentration in the liver was increased by 14 days PS exposure, whereas its concentration in the hippocampus was decreased by 7 and 14 days of PS exposure. There were no significant changes in zinc concentration in the heart, spleen, kidney, duodenum, cortex, and cerebellum. A decrease in the zinc apparent absorption was observed in the 7- and 14-day PS groups. The increased serum CORT and liver zinc concentrations and decreased serum zinc and apparent absorption of zinc recovered to normal concentrations 7 days away from PS exposure. The results suggest that PS could induce lower serum zinc, which might be correlated with decreased zinc absorption in the small intestine and increased liver zinc accumulation after PS exposure. The consequent effects of decreased hippocampal and serum zinc and increased CORT concentration after PS exposure on stress-related diseases await further research.     

Protective Effect of Tubotaiwine on Cadmium-Induced Hypertension in Rats through Reduction in Arterial Stiffness and Vascular Remodeling

Doklady Biochemistry and Biophysics - Humans are adversely affected by exposure to cadmium (Cd) as it induces oxidative stress which damages kidneys, bones pulmonary tissues, liver, cardiovascular,...     

Skeletal Muscle Abnormalities in Pulmonary Arterial Hypertension

Background

Pulmonary arterial hypertension is a progressive disease that is characterized by dyspnea and exercise intolerance. Impairment in skeletal muscle has recently been described in PAH, although the degree to which this impairment is solely determined by the hemodynamic profile remains uncertain. The aim of this study was to verify the association of structural and functional skeletal muscle characteristics with maximum exercise in PAH.

Methods

The exercise capacity, body composition, CT area of limb muscle, quality of life, quadriceps biopsy and hemodynamics of 16 PAH patients were compared with those of 10 controls.

Results

PAH patients had a significantly poorer quality of life, reduced percentage of lean body mass, reduced respiratory muscle strength, reduced resistance and strength of quadriceps and increased functional limitation at 6MWT and CPET. VO₂ max was correlated with muscular variables and cardiac output. Bivariate linear regression models showed that the association between muscular structural and functional variables remained significant even after correcting for cardiac output.

Conclusion

Our study showed the coexistence of ventilatory and quadriceps weakness in face of exercise intolerance in the same group of PAH patients. More interestingly, it is the first time that the independent association between muscular pattern and maximum exercise capacity is evidenced in PAH, independently of cardiac index highlighting the importance of considering rehabilitation in the treatment strategy for PAH.