尿酸与心血管疾病的关系

尿酸(uric acid, UA)是人体内嘌呤代谢的终产物。在心血管系统中,尿酸可激活肾素-血管紧张素系统、引起内皮细胞功能障碍及炎症反应,与心血管疾病的发生发展相关。本文就尿酸的生理功能、与心血管疾病(高血压、心房颤动、动脉粥样硬化、冠心病、急性心肌梗死)之间的关系及临床药物研究进展进行综述,概述目前高尿酸血症与心血管疾病相关研究进展,阐述二者之间的相关性,有利于早期诊疗心血管疾病,预防心血管疾病不良事件发生给患者带来的危害。     

焦磷酸盐与血管钙化

血管钙化是指促钙化因子与抑钙化因子失衡导致钙磷在血管壁的异常沉积,与心血管疾病的高发病率与高死亡率密切相关。细胞外焦磷酸盐作为内源性羟磷灰石结晶形成的抑制剂,在血管钙化的发生中发挥重要的作用。近年来的研究发现,焦磷酸盐代谢异常是导致某些家族遗传性疾病及慢性肾病患者发生血管钙化的重要机制。本文着重对焦磷酸盐在体内的代谢、焦磷酸盐及其代谢相关酶在血管钙化发生中的作用进行综述。     

高尿酸血症与高血压病相关性的研究进展

尿酸是人体内嘌呤代谢的最终产物,当尿酸生成增多和/或排出减少时,均可引起血中尿酸盐浓度增高。当血尿酸水平男性大于7.0 mg/dl,女性大于6.0 mg/dl称为高尿酸血症。作为嘌呤代谢紊乱所致疾病,高尿酸血症以往仅侧重于痛风性关节炎、痛风石沉积和肾尿酸结石形成等的诊断与治疗。目前新近研究表明:高尿酸血症可能是高血压病的独立危险因素之一且尿酸水平增高通常早于高血压的发生与进展,干预尿酸水平有望成为高血压治疗的新靶点,随着高血压研究的全球化深入,对于尿酸及尿酸水平增高的流行病学、基础学与临床方面的研究也日益备受关注。基于此,本文对尿酸的合成与代谢;高尿酸血症成因及其与高血压的流行病学研究;高尿酸血症通过引发一氧化氮合成水平减低、血管平滑肌细胞生物学行为改变、机体炎症与氧化应激反应及肾素-血管紧张素系统激活等方面所致高血压的发病机制;高尿酸血症干预治疗对于高血压病的转归进行简要综述。     

尿酸与DNA损伤之间关系的研究进展

尿酸是人体嘌呤代谢的最终产物，高于生理浓度的尿酸通常伴随细胞内氧化应激和活性氧(reactive oxygen species, ROS)增多，进而造成细胞内DNA损伤。DNA损伤反应及其引起的细胞死亡会促进内源性嘌呤增多，进一步导致尿酸升高。同时，DNA损伤反应可引起炎症、胰岛素抵抗、脂质代谢等异常，从而导致糖尿病、慢性肾脏疾病、非酒精性脂肪肝病等疾病的发生。这可能是高浓度尿酸成为多种慢性代谢性疾病独立危险因素的原因之一。因此，研究尿酸与DNA损伤之间的关系有助于深入了解尿酸的生理功能，为预防高尿酸血症及其相关疾病，并寻找潜在治疗靶点提供理论依据。     

代谢综合征各组分聚集对尿酸与肾功能减退之间关系的影响

目的：在代谢综合征各组分聚集逐渐增强的情况下,探讨尿酸与肾功能减退之间关系的变化趋势。方法：选取2016年1—12月期间到北京某体检中心进行健康体检的人作为研究对象（共2 020人）,在男性和女性中分别按照代谢综合征各组分聚集不同分为Normal组（无代谢综合征组分）、Factor 1组（1个代谢综合征组分）、Factor 2组（2个代谢综合征组分）、Factor 3组（3或4个代谢综合征组分）,比较不同组中尿酸升高与肾功能减退之间的关系。结果：参检人群高尿酸血症和肾功能减退患病率随代谢综合征聚集因素增加呈递增趋势,但女性患病率低于男性;在多重线性回归模型下,尿酸与肾小球滤过率拟合直线的斜率呈增大趋势,即尿酸每增加1个单位所带来肾小球滤过率减低量在增加。在多元Logistic回归模型中,尿酸升高所带来的肾功能减退风险也随聚集因素的增多而递增。结论：在不同人群中,尿酸导致肾功能减退的风险不同;代谢综合征各组分因子聚集增强,尿酸引起肾功能损伤的风险也会增大。     

肥胖所致心肌重构及相关线粒体稳态失衡机制研究进展

肥胖是心血管疾病的重要危险因素,可导致心肌重构等多种心血管疾病。肥胖可影响血流动力学、破坏自主神经平衡、诱导脂肪组织功能障碍和线粒体稳态失衡,从而损伤心肌功能。代谢稳态所需的关键生物化学反应主要发生在线粒体中,线粒体稳态是决定细胞活力的关键因素之一。线粒体稳态的平衡由线粒体分裂和融合、线粒体嵴重构、线粒体生物合成、线粒体自噬、线粒体氧化应激等动态过程调节。线粒体分裂和融合以及线粒体嵴形态不断变化以维持线粒体结构的完整性,且线粒体通过生物合成和自噬降解以维持"健康"的线粒体状态,而活性氧簇可作为信号分子调控细胞内信号转导。肥胖时的脂质过度沉积及脂质合成与分解不平衡诱发线粒体结构和功能的稳态失衡,激活细胞凋亡级联反应并导致心肌重塑。本文就肥胖所致心肌重构的可能机制以及线粒体稳态失衡在其中的重要作用作一简要综述,以期为临床上肥胖所致心血管疾病的防治提供重要策略和潜在靶点。     

粪菌移植的临床应用研究进展

人类的肠道菌群种类及数量众多,目前被认为是人体的一个特殊器官。肠道菌群在维持肠道的正常生理功能和机体免疫功能方面发挥了重要作用,肠道微生态失衡与炎症性肠病、代谢综合征、肝病、心血管疾病、精神疾病、关节炎等多种肠内外疾病密切相关,纠正肠道微生态失衡将有助于上述疾病的治疗。粪菌移植(fecal microbiota transplantation,FMT)是指将健康人粪便中的功能菌群移植到患者胃肠道内,重建具有正常功能的肠道菌群,以达到治疗肠道和肠道外疾病的目的。目前报道FMT已应用于艰难梭菌感染、炎症性肠病、肠易激综合征、代谢综合征等多种疾病的治疗中。本文就FMT的临床应用现状作一综述。     

脂肪因子与代谢综合征关系的研究进展

代谢综合症是一系列代谢和心血管功能失调的临床特征,包括中心性肥胖、高血压、血脂异常、高血糖及胰岛素抵抗等,其发病机制及如何预防及控制代谢综合症正日益成为目前的学术热点。目前已经公认,脂肪不仅是能量存储器官,也是一个重要的内分泌器官。脂肪组织分泌的生物活性分子被称为脂肪因子。近年来的研究表明,脂肪因子广泛参与肥胖、2型糖尿病、高血压病及心血管疾病等一系列代谢相关性疾病的病理生理过程。脂肪因子能通过介导一系列的信号转导通路,并广泛参与机体复杂的代谢平衡网络的调节。脂肪因子的失衡能导致机体发生对胰岛素敏感性改变等一系列的生物学反应,从而在肥胖和代谢综合症的病理过程中发挥重要的作用。本文综述了脂肪因子与代谢综合征的关系的研究进展。     

肠道菌群失调与高尿酸血症关系的研究进展

高尿酸血症（hyperuricemia,HUA）是一种涉及肝、肾、肠等多个器官的代谢性疾病，因尿酸代谢异常而引起代谢障碍。尿酸在肝脏和肾脏中的代谢途径目前已经被阐明，但在肠道内的代谢途径尚未完全清晰。肠道菌群在人体肠道中定植，与宿主存在互惠共生的关系，在宿主的代谢和免疫调节中起着至关重要的作用。肠道菌群结构的变化可能引起代谢紊乱，肠道菌群参与嘌呤代谢酶的合成和炎症因子的释放，与HUA的发生发展密切相关。肠道菌群作为探讨HUA发病机制的切入点，已成为新的研究热点。本综述主要阐述HUA与肠道菌群之间的关系，探讨肠道菌群抗HUA的机制，如肠道菌群促进嘌呤和尿酸分解代谢，影响尿酸排泄，以及HUA引起的肠道炎症反应等，以期为通过调节肠道菌群来治疗HUA提供一定的依据。     

微生物代谢产物在心血管疾病中的应用

心血管疾病严重威胁着人类健康,研发防治心血管疾病的有效药物一直是广大研究者研究的焦点。微生物的多种代谢产物在预防和治疗心血管疾病方面得到广泛应用,从微生物代谢产物中寻找预防和治疗心血管疾病的药物是比较传统而且简单的方法,文章就微生物代谢产物在心血管疾病方面的应用进行了阐述。     

Uric Acid: The Oxidant-Antioxidant Paradox

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.     

Xanthine Oxidase Inhibition by 1,3-dipropyl-8-sulfophenyl-xanthine (DPSPX), an Antagonist of Adenosine Receptors

Xanthine oxidase (XO), an enzyme involved in purine metabolism, is a source of either oxidants (superoxide radical) or antioxidants (uric acid). Interference with XO activity can lead to oxidative stress, thus contributing to the pathogenesis of cardiovascular diseases. The adenosine receptors antagonist, 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), induces hypertension and cardiovascular injury in rats. Since DPSPX is a xanthine, we aimed at evaluating DPSPX's influence on XO activity to ascertain its contribution to DPSPX-induced hypertension. The activity of isolated XO in the presence of DPSPX was evaluated spectrophotometrically. Serum and urinary uric acid levels of DPSPX-treated rats were measured using a commercial kit. DPSPX inhibited XO activity in a concentration-dependent manner and reduced rat serum and urinary uric acid levels. It can be concluded that: DPSPX is an inhibitor of XO; decreased generation of uric acid may lead to oxidative stress, thus contributing to endothelial dysfunction and vascular morphological changes in DPSPX-treated rats.     

Xanthine oxidase inhibition by 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), an antagonist of adenosine receptors

Xanthine oxidase (XO), an enzyme involved in purine metabolism, is a source of either oxidants (superoxide radical) or antioxidants (uric acid). Interference with XO activity can lead to oxidative stress, thus contributing to the pathogenesis of cardiovascular diseases. The adenosine receptors antagonist, 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), induces hypertension and cardiovascular injury in rats. Since DPSPX is a xanthine, we aimed at evaluating DPSPX's influence on XO activity to ascertain its contribution to DPSPX-induced hypertension. The activity of isolated XO in the presence of DPSPX was evaluated spectrophotometrically. Serum and urinary uric acid levels of DPSPX-treated rats were measured using a commercial kit. DPSPX inhibited XO activity in a concentration-dependent manner and reduced rat serum and urinary uric acid levels. It can be concluded that: DPSPX is an inhibitor of XO; decreased generation of uric acid may lead to oxidative stress, thus contributing to endothelial dysfunction and vascular morphological changes in DPSPX-treated rats.     

腺苷酸活化蛋白激酶在脂联素心血管保护效应中的作用

脂联素是主要由白色脂肪组织分泌的一种活性多肽,具有调节脂肪酸和葡萄糖代谢、抗炎、减轻动脉粥样硬化等多种生物学功能,血浆脂联素含量降低参与了代谢性疾病及心血管疾病的发生、发展。腺苷酸活化蛋白激酶（AMP．activated protein kinase,AMPK）是脂联素信号通路中的关键信号分子,本文就其在脂联素心血管保护效应中的作用作一综述,介绍脂联素改善糖、脂代谢紊乱、动脉粥样硬化、心力衰竭及心肌缺血,再灌注损伤作用机制的新进展。     

痛风性关节炎动物模型的研究现状与展望

痛风是由于机体嘌呤代谢紊乱,导致血内尿酸增高和/或肾脏排泄尿酸减少,从而引起尿酸盐在组织沉积的疾病,目前尚未见在实验动物中复制出类似人类的痛风性关节炎模型。通过对目前国内外高尿酸血症及痛风模型复制的方法、机制和应用的研究,分析各自的特点及不足之处,并提出复制更加符合临床的高尿酸血症及痛风性关节炎动物模型的展望与设想。     

Uric acid inhibition of dipeptidyl peptidase IV in vitro is dependent on the intracellular formation of triuret

Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid will have on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr) CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV, respectively. Finally, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases.     

综述: HDL蛋白质组分临床研究新进展

高密度脂蛋白胆固醇(HDL-C)水平与冠心病风险呈负相关,低HDL-C水平增加心血管疾病风险,是心血管疾病的独立危险因素．然而升高HDL-C水平的药物治疗并没有明显的临床获益,没有起到降低心血管疾病风险的预期效果,因此高密度脂蛋白(HDL)功能比HDL-C水平更好地预测心血管事件的发生．HDL是蛋白质含量最高的脂蛋白,由于蛋白质组学技术的进步,越来越多的HDL蛋白质成分被发现,除了传统的载脂蛋白、酶类,还包括脂质转移蛋白、急性期反应蛋白、补体成分、蛋白酶抑制剂,HDL的功能也从脂质转运扩展到感染免疫、急性期反应、补体激活、离子结合等,不仅参与动脉粥样硬化的发生发展,在终末期肾病、糖尿病等高心血管风险疾病中也发挥重要作用．本文就HDL蛋白质成分、功能及在冠心病和高心血管风险疾病中的作用做一综述．     

胆汁酸受体FXR 的研究进展

法尼酯衍生物X受体(FXR)是一种胆汁酸受体,在胆汁酸代谢和胆固醇代谢中发挥重要作用,并有望成为降低胆固醇,治疗某些心血管病及肝脏疾病的治疗靶点。本文介绍了FXR的发现、FXR在调控胆汁酸和脂质代谢中的作用,以及FXR在心血管疾病治疗中的应用前景。     

Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation?

Cardiovascular diseases remain an important cause of morbi-mortality. Atherosclerosis, which predisposes to cardiovascular disorders such as myocardial infarction and stroke, develops silently over several decades. Identification of circulating biomarkers to evaluate cardiovascular event risk and pathology prognosis is of particular importance. Microparticles (MPs) are small vesicles released from cells upon apoptosis or activation. Microparticles are present in blood of healthy individuals. Studies showing a modification of their concentrations in patients with cardiovascular risk factors and after cardiovascular events identify MPs as potential biomarkers of disease. Moreover, the pathophysiological properties of MPs may contribute to atherosclerosis development. In addition, pharmacological compounds, used in the treatment of cardiovascular disease, can reduce plasma MP concentrations. Nevertheless, numerous issues remain to be solved before MP measurement can be applied as routine biological tests to improve cardiovascular risk prediction. In particular, prospective studies to identify the predictive values of MPs in pathologies such as cardiovascular diseases are needed to demonstrate whether MPs are useful biomarkers for the early detection of the disease and its progression.     

Reactions of Peroxynitrite with Uric Acid: Formation of Reactive Intermediates,Alkylated Products and Triuret,and In Vivo Production of Triuret Under Conditions of Oxidative Stress

Hyperuricemia is associated with hypertension, metabolic syndrome, preeclampsia, cardio-vascular disease and renal disease, all conditions associated with oxidative stress. We hypothesized that uric acid, a known antioxidant, might become prooxidative following its reaction with oxidants; and, thereby contribute to the pathogenesis of these diseases. Uric acid and 1,3-¹⁵N₂-uric acid were reacted with peroxynitrite in different buffers and in the presence of alcohols, antioxidants and in human plasma. The reaction products were identified using liquid chromatography-mass spectrometry (LC-MS) analyses. The reactions generate reactive intermediates that yielded triuret as their final product. We also found that the antioxidant, ascorbate, could partially prevent this reaction. Whereas triuret was preferentially generated by the reactions in aqueous buffers, when uric acid or 1,3-¹⁵N₂-uric acid was reacted with peroxynitrite in the presence of alcohols, it yielded alkylated alcohols as the final product. By extension, this reaction can alkylate other biomolecules containing OH groups and others containing labile hydrogens. Triuret was also found to be elevated in the urine of subjects with preeclampsia, a pregnancy-specific hypertensive syndrome that is associated with oxidative stress, whereas very little triuret is produced in normal healthy volunteers. We conclude that under conditions of oxidative stress, uric acid can form reactive intermediates, including potential alkylating species, by reacting with peroxynitrite. These reactive intermediates could possibly explain how uric acid contributes to the pathogenesis of diseases such as the metabolic syndrome and hypertension.