摘要
越来越多的证据表明活性氧的过度生产在心脑血管疾病的发展中起到重要作用。被认定为在血管壁上产生氧化应激的机制中,由膜结合的NAD(P)H氧化酶类所介导机制是一个主要代表。NAD(P)H氧化酶类是一个既在吞噬细胞又在非吞噬细胞中产生ROS的酶家族。血管的NAD(P)H氧化酶包括膜结合亚基Nox1,Nox2(gp91phox),Nox4和p22phox,以及氧化酶的催化部位和p47phox和p67phox的细胞组分。Rac1(与Ras相关的C3肉毒毒素基质)是一种小型的GTP酶,这种酶对NADPH酶的集合和活化是必要的。一些分子和细胞的研究报道了Rac1在不同的心血管疾病中作用,例如血管平滑肌增殖、心肌细胞肥大、内皮细胞形态变化、动脉粥样硬化和高血压内皮功能紊乱。此外,由Rac1引起的DADPH活性的增加已经在动物和人类心肌梗死和心力衰竭模型上被报道。Rac1/NADPH途径已经被发现参与不同的脑部疾病,例如缺血性中风、认知功能障碍、蛛网膜下腔出血和一些神经退行性疾病的神经元损伤。另外,血栓性疾病是心血管和脑血管疾病发病中的一个重要步骤。Rac1也被发现参与血小板活化,诱导鸡蛋白聚合和板状伪足的形成,这些是血小板形成的必要步骤。总之,候选者Rac1作为一种新的心脑血管疾病的药理学靶标。Rac1参与药物例如他汀类药物有益的多效性环节是众所周知的,许多副作用的出现也已经引发了对一些病人组织的管理。有趣的是,一个新型的选择性的Rac抑制剂,NSC23766最近被介绍了;报道称它主要被应用于肿瘤领域被。继续进一步的研究是必需的,以期能够扩展它在心脑血管疾病方面的应用,并将其应用于人类。
关键词: Rac-1,NSC23766,氧化应激,NADPH氧化酶,心血管,脑血管
图形摘要
Current Drug Targets
Title:Rac-1 as a New Therapeutic Target in Cerebro- and Cardio-Vascular Diseases
Volume: 15 Issue: 13
Author(s): Albino Carrizzo, Maurizio Forte, Maria Lembo, Luigi Formisano, Annibale A. Puca and Carmine Vecchione
Affiliation:
关键词: Rac-1,NSC23766,氧化应激,NADPH氧化酶,心血管,脑血管
摘要: Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in the development of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress in the vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases are a family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidase contains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, and the cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essential for the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvement of Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocyte hypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increased activation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction and heart failure. The Rac1/NADPH pathway has also been found involved in different pathologies of the cerebral district, such as ischemic stroke, cognitive impairment, subaracnoid hemorrhage and neuronal oxidative damage typical of several neurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovascular diseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodia formation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a new pharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficial pleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concern for the management of some patient groups. Interestingly, a novel selective Rac1 inhibitor, NSC23766, has recently been introduced; its use has been reported mainly in the oncology field. Future studies are needed to extend its application to cardio- and cerebro-vascular diseases, and translate its use to humans.
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Albino Carrizzo, Maurizio Forte, Maria Lembo, Luigi Formisano, Annibale A. Puca and Vecchione Carmine, Rac-1 as a New Therapeutic Target in Cerebro- and Cardio-Vascular Diseases, Current Drug Targets 2014; 15 (13) . https://dx.doi.org/10.2174/1389450115666141027110156
DOI https://dx.doi.org/10.2174/1389450115666141027110156 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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