Klotho蛋白在慢性肾脏病及其心血管并发症中的作用

Klotho蛋白是一种与人类衰老表型相关的肽类化合物,其生物学功能多样,主要表达在肾脏及大脑。慢性肾脏病(chronic kidney disease,CKD)是指各种原因引起的慢性肾脏结构和功能障碍(肾脏损害病史大于3个月),包括肾GFR正常和不正常的病理损伤、血液或尿液成分异常,及影像学检查异常,或不明原因GFR下降(60ml/min·1.73m2)超过3个月。近年来,国内外大量研究证实Klotho蛋白与CKD关系密切,CKD患者的Klotho呈低表达状态,Klotho蛋白作为肾脏的保护因子参与肾损伤修复,低Klotho水平是肾脏结构及功能受损的指标。除了作用于肾脏,Klotho蛋白缺乏还通过诱导血管内皮损伤、氧化应激、炎症反应等多种机制参与心血管疾病的演变。     

血管紧张素1-7与心血管疾病的关系

血管紧张素1-7是一种具有重要生物学作用的血管紧张素家族的终末活性产物,其通过受体介导表现为舒张血管、降低血压、利尿、利钠和抑制平滑肌增殖等作用,为临床心血管疾病的防治提供了新的思路.本文就血管紧张素1-7的生化、生理特性及其与心血管疾病的关系作一扼要综述.     

血管紧张素1—7与心血管疾病的关系

血管紧张素1—7是一种具有重要生物学作用的血管紧张素家族的终末活性产物，其通过受体介导表现为舒张血管、降低血压、利尿、利钠和抑制平滑肌增殖等作用，为临床心血管疾病的防治提供了新的思路。本文就血管紧张素1—7的生化、生理特性及其与心血管疾病的关系作一扼要综述。     

Klotho蛋白与动脉粥样硬化的关系

Klotho蛋白是一种与寿命和衰老表型相关的肽类激素,Klotho基因具有单核苷酸多态性,并存在动脉粥样硬化的易感基因型。Klotho蛋白通过膜结合型和分泌型两种形式在体内发挥生物学效应。Klotho基因在小鼠中表达缺陷时会引起一系列类似动脉粥样硬化的表现,机制可能为Klotho调节成纤维细胞生长因子23通路、抗氧化应激、抗凋亡、血管钙化、增加一氧化氮合成、上调血管紧张素转化酶、改善内皮功能等影响血管功能和血栓形成共同起到抗动脉粥样硬化作用,从而保护心血管系统。     

Klotho 在老化和癌症中的研究进展

老化和肿瘤密切相关,癌症发生与细胞老化过程涉及的分子通路互相交联.Klotho是新的抗衰老基因,参与体内广泛的生物学过程,影响体内多条信号通路;Klotho除了具有抗衰老作用外,还与癌症的发生、发展紧密联系.本文就Klotho的最新研究进展作一综述,旨在探索Klotho与老化和癌症之间潜在的关系,为衰老和肿瘤的研究提供新思路.     

衰老相关基因Klotho的研究进展

<正>随着衰老研究及分子生物学的迅猛发展,衰老机制的研究已经走向分子与基因水平。Klotho基因是哺乳动物体内第一个过表达延长生命、低表达加速衰老的衰老抑制基因。Klotho基因在抗衰老及衰老相关疾病的发生中发挥着极为重要的作用,现将这方面的研究综述如下。1 Klotho基因的生物学属性Kuro-o等~〔1〕首次从衰老小鼠中成功克隆Klotho基因,随之发现大鼠和人也有Klotho基因,且它们之间具有较高(83%)的     

人血清胎球蛋白A在COPD中的作用

COPD是一种慢性炎症性疾病,这种持续低水平的系统性炎症可能与其并发症,如心血管疾病、代谢综合征、骨质疏松等有密切关系.人血清胎球蛋白A具有抗炎及抑制血管钙化的生物学作用,可能与COPD的炎症反应及其合并症有关,认识人血清胎球蛋白A在COPD中的作用,可能为COPD患者的诊断和治疗提供新的思路.     

Klotho和成纤维细胞生长因子23对肾素血管紧张素系统的分析

<正>背景:Klotho是成纤维细胞生长因子(FGF-23)的重要共同受体,对肾素血管紧张素系统有潜在的抑制作用。关于Klotho和FGF-23水平联合预测血管紧张素转换酶抑制获益的数据有限。方法:共有3555例稳定缺血性心脏病和左心室射血分数40%患者参加了PEACE试验(群多普利vs安慰剂)。随机分组时提取了参与者Klotho和FGF-23水平(四分位数)。在安慰剂组中,计算了心血管死亡或心力衰竭住院及其组成部分的6年Kaplan-Meier发生率和调整后的风险。结果:与高     

血管抑素和内皮抑素与冠心病的关系

近年来不断发现的新的内源性血管抑制因子，提示在人体内存在与凝血/纤溶系统类似的血管生成/抑制系统。本文就血管抑制因子中的血管抑素和内皮抑素的来源、生物学特性，与已知血管新生因子的关系、作用机制，及与冠脉粥样硬化、冠脉侧枝循环、冠脉成形术后再狭窄等方面作一综述。     

花生四烯酸细胞色素P450表氧化酶代谢产物环氧二十碳三烯酸生物学作用

对于花生四烯酸经细胞色素P450表氧化酶作用生成的环氧二十碳三烯酸（EETs）,最初在心血管及肾脏系统中被广泛研究,并发现EETs的舒张血管、抑制血小板的聚集、抑制血管平滑肌细胞的炎症反应及平滑肌细胞的迁移、增强纤维蛋白的溶解等作用,为预防及治疗许多心血管疾病如高血压、动脉粥样硬化等提供了新的研究方向。近来研究发现EETs具有促进机体肿瘤细胞的增殖、迁移等作用,其有可能使EET成为肿瘤治疗的新靶点。深入研究EETs的生物学作用及其作用机制,将为临床治疗某些疾病提供新的思路。     

Implications of Klotho in vascular health and disease

Cardiovascular disease (CVD) is a prevalent condition in general population and the first cause of death overall. Klotho, a pleiotropic protein related to longevity that acts as a co-receptor of the fibroblast growth factor 23, has been proposed as a key regulator of the development of CVD. In the few clinical studies made, it has been observed a relationship between low levels of soluble Klotho and the occurrence and severity of CVD, as well as a reduction of cardiovascular risk when they are high. Also, different polymorphisms of human Klotho gene have been related to the incidence of cardiovascular events. Moreover, several experimental studies indicate that this protein acts in the maintenance of vascular homeostasis. Klotho improves endothelial dysfunction through promotion of NO production and mediates anti-inflammatory and anti-aging effects such as suppression of adhesion molecules expression, attenuation of nuclear factor-kappa B or inhibition of Wnt signaling. Furthermore, this protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy. The expression of this protein in the vascular wall implies a new scenario for the treatment of vascular disorders. The purpose of this review is to provide an overview of the relationship between the Klotho protein and CVD, in addition to its role in the maintenance of functional vascular integrity.     

Cellular mechanism of vasculo-protection induced by polyphenols on the endothelium

Epidemiological studies have suggested that dietary factors, including moderate red wine consumption, might reduce the risk of cardiovascular diseases. The beneficial effect of fruits, vegetables, or red wine may be in part explained by the presence of polyphenols with a multitude of biological activities, including antioxidant and free radical-scavenging properties, anti-aggregatory platelet property and inhibition of vascular smooth muscle cell proliferation. Another therapeutically relevant effect of polyphenols may be their ability to interact with the generation of nitric oxide from vascular endothelium that leads not only to vasodilatation but also to the expression of genes protective of the cardiovascular system. Finally, polyphenols contribute to the preservation of endothelial integrity by acting on the processes implicated in endothelial proliferation, migration and apoptosis. All these effects of polyphenols might interfere with atherosclerotic plaque development and stability, vascular thrombosis and occlusion and therefore might explain their cardio- and vascular protective properties.     

Impaired function of fibroblast growth factor 23 / Klotho protein axis in prediabetes and diabetes mellitus: Promising predictor of cardiovascular risk

The discovery of clear molecular mechanisms of early cardiac and vascular complications in patients with prediabetes and known diabetes mellitus are core element of stratification at risk with predictive model creation further. Previous clinical studies have shown a pivotal role of impaired signaling axis of fibroblast growth factor 23 (FGF23), FGF23 receptor isoforms and its co-factor Klotho protein in cardiovascular (CV) complications in prediabetes and diabetes. Although there were data received in clinical studies, which confirmed a causative role of altered function of FGF-23/Klotho protein axis in manifestation of CV disease in prediabetes and type 2 diabetes mellitus (T2DM), the target therapy of these diseases directing on improvement of metabolic profiles, systemic and adipokine-relating inflammation by beneficial restoring of dysregulation in FGF-23/Klotho protein axis remain to be not fully clear. The aim of the review was to summarize findings regarding the role of impaired FGF-23/Klotho protein axis in developing CV complications in patients with prediabetes and type 2 diabetes mellitus. It has been elucidated that elevated levels of FGF-23 and deficiency of Klotho protein in peripheral blood are predictors of CV disease and CV outcomes in patients with (pre) diabetes, while predictive values of dynamic changes of the concentrations of these biomarkers require to be elucidated in detail in the future.     

Genomics and proteomics: a new approach for assessing thrombotic risk in autoimmune diseases

Several systemic autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome, are characterised by enhanced atherosclerosis and, consequently, higher cardiovascular morbidity and mortality rates. The association of these diseases with atherosclerosis suggests a common pathogenic mechanism. Genomic and proteomic studies performed on atherosclerotic plaques have further confirmed the presence of a gene and protein profile similar to that observed in autoimmune diseases with cardiovascular risks. Human sera and body fluids have been analysed and have resulted in the identification of auto-antibodies that can be used as diagnostic markers in specific autoimmune diseases, and proteomic fingerprints of blood cells, tissues and body fluids have resulted in the identification of individual proteins or patterns of protein expression that are deregulated. The information provided by these proteomic studies is of diagnostic and therapeutic potential. In this review, we discuss new approaches available for assessing thrombotic risk in autoimmune diseases, focusing in the genomic and proteomic methods now available to deep into the origin of the mechanisms associated with vascular involvement in systemic autoimmune diseases. The increasing data available suggests that when treating patients with these autoimmune disorders, paying attention to the increased risk of cardiovascular disease is essential.     

Gender differences in vascular medicine

In vascular medicine only a few studies concerning gender differences in vascular diseases, course of the disease and therapy exist. Risk factors are allocated differently between men and women with different influences on cardiovascular diseases. Diabetic women do have a particular high risk. The proportion of women smokers with a risk for aggravation of the other risk factors is increased. In young female smokers the hypoplastic aortoiliac syndrome is a special course of peripheral arterial disease associated with a bad prognosis. The benefit of hormone replacement therapy in vascular diseases of postmenopausal women has not yet been demonstrated. On the other hand testosterone seems to have a favourable effect on vascular diameter and endothelium of coronaries. Women with peripheral arterial disease represent high risk patients with a particular risk for cardiovascular letality. Periprocedural complications of the analysed operations or interventions are found more frequent in women. Furthermore the disease is in an advanced stage when treated. Especially men with asymptomatic high grade carotid stenosis benefit more from an operation than women because of the higher risk for ischemic stroke. Unfortunately the benefit of the operation in women is neutralized by the higher rate of periprocedural complications. Some studies demonstrate the gender bias in treatment: women seldom receive revascularisation and guideline therapy as frequently as men. The same is true with thromboembolic prophylaxis concerning in hospital patients. In pharmacotherapy women have in result of metabolism more side effects. Additionally women are underrepresented in drug admission studies compared to their percentage of population and gender prevalence of diseases. Further studies concerning gender differences in vascular medicine are definitely needed.     

Corcoran Lecture. Cardiovascular genomics and oxidative stress

The majority of modifiable cardiovascular risk factors are complex, polygenic, or at least oligogenic traits, with genetic and environmental determinants playing important roles in disease risk and its phenotypic expression. The Human Genome Project and subsequent mouse and rat genome data have provided powerful tools to commence the dissection of genetic determinants of hypertension and other cardiovascular risk factors. Despite several new methodologies such as genome-wide scans, genome-wide gene expression profiling, and proteomic screens, it is fair to say that the progress of genetic studies designed as nonhypothesis driven has been relatively slow. On the other hand, several interesting candidate pathways have been identified, where investigators allowed for hypothesis-driven functional studies. One example of such pathway is vascular oxidative stress with its extensive network of genes and proteins, many with proven contributions to cardiovascular disease. Therefore, in parallel to genome-wide or proteome-wide studies, it will be constructive to pursue "pathwayomics" defined here as functional studies of a candidate pathway for disease pathogenesis.     

Gout,Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect?

Gout and hyperuricemia have long been suspected to be risk factors for cardiovascular disease. However, studies have frequently failed to distinguish whether these entities have an independent effect on cardiovascular risk or serve as markers for other risk factors. In vitro and animal studies suggest that uric acid is a biologically active compound that can increase inflammatory mediators known to lead to vascular damage. In contrast, uric acid also has potentially protective effects as a strong antioxidant, approaching the potency of vitamin C. Large clinical trials demonstrate a consistent relationship between elevated serum uric acid and a variety of cardiovascular diseases, although the strength of association varies greatly. We review the evidence for and against an independent role for hyperuricemia and/or gout in cardiovascular pathology.     

Hypertension control: multifactorial contributions

Treatment of hypertension reduces the risk of several associated deleterious conditions, although it does not lower risk for all cardiovascular diseases. A new theory suggests that high blood pressure is but one piece in the puzzle of a complex syndrome of inherited risk factors called the hypertension syndrome. Several new findings have emerged theorizing that patients may have coronary artery disease before the actual onset of elevated blood pressure. Epidemiologic studies have found that normotensive patients with a family history of hypertension often have a disease process and prognosis similar to that of hypertensives. It seems that some patients may “inherit” abnormalities that make them prone to the development of hypertension, as well as a complex series of cardiovascular disease risk factors. These include elevated lipids, increased left ventricular hypertrophy, arterial stiffening, insulin resistance, renal function abnormalities, and neuroendocrine changes. It is conceivable that the hypertension syndrome may be reversible if the disease process is diagnosed early, which appears to be well before the actual onset of high blood pressure. High blood pressure may be a risk marker for irreversible vascular disease and early detection of the many components of hypertension syndrome may delay or prevent cardiovascular disease from developing in high-risk patients.     

Klotho及其基因多态性与衰老相关性疾病关系研究进展

Klotho基因是一种与寿命和衰老表型（如动脉硬化、骨质疏松、肺气肿等）相关的基因,该基因缺陷的小鼠会出现与人类衰老相似的临床表型。随着增龄,与衰老相关性疾病也日益增多,成为影响人类健康长寿的重要因素,为此本文从分子遗传学角度上就klotho基因及其多态性与衰老相关性疾病的关系研究进展做综合分析,以寻求该基因在衰老相关性疾病的发生和发展中所起作用的线索。     

Cardiovascular risks in spondyloarthritides

PURPOSE OF REVIEW: Spondyloarthritides are associated with increased cardiovascular risks, which can only partly be explained by traditional risk factors. It is likely that the chronic inflammatory state is involved. In this review, novel findings regarding cardiac and vascular pathologies and potential overlapping mechanisms will be discussed. RECENT FINDINGS: Cardiac pathologies in spondyloarthritides are conduction disturbances and valvular heart diseases. Recent studies have also focused on vascular pathologies and showed impaired endothelial function, suggesting that atherosclerotic alterations could also be involved in increased cardiovascular mortality. Novel findings suggest that chronic systemic inflammation is involved in these cardiac and vascular pathologies. Thus, spondyloarthritides and ankylosing spondylitis are associated with increased levels of circulating inflammatory mediators such as C-reactive protein. Interestingly, ankylosing spondylitis patients may also have an atherogenic lipid profile and disturbances in their T-helper lymphocyte subsets, which may be involved in cardiovascular disease development. The beneficial effects of statin treatment on circulating inflammatory mediators and atherogenic lipid profiles may reveal new therapeutic options for patients with spondyloarthritides. SUMMARY: Recent studies have highlighted that the chronic, systemic inflammatory condition of patients with spondyloarthritides may be involved in the development of cardiac and vascular pathologies.