Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes , Homburg, Germany .
Antioxid Redox Signal. 2014 Mar 10;20(8):1238-50. doi: 10.1089/ars.2013.5526. Epub 2013 Sep 19.
HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation.
Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.
Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood.
Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1-specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies.
羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）降低血清胆固醇浓度，有益于冠心病的一级和二级预防。其他降脂干预措施仅部分再现了其积极的临床效果，这表明他汀类药物除了降低胆固醇外，还有潜在的作用。在实验模型中，已经记录了通过抑制异戊烯而介导的直接有益的心血管作用，异戊烯作为细胞内信号分子（如小 Rho 鸟苷三磷酸结合蛋白）的脂质附着物，其膜定位和功能依赖于异戊烯化。
Rac1 GTP 酶是细胞运动的既定主调节剂，通过皮质肌动蛋白的重组，以及通过调节烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性产生活性氧。
细胞、动物和人类的观察结果表明，Rac1 GTP 酶的激活是心血管病理学的一个关键组成部分，包括内皮功能障碍、心肌肥大和纤维化、心房颤动、中风、高血压和慢性肾病。然而，潜在的信号转导仍不完全清楚。
基于最近在心血管系统中 Rac1 研究的进展，使用过表达激活型 Rac1 或条件性敲除的转基因小鼠模型以及 Rac1 特异性小分子抑制剂 NSC 23766，对 Rac1 介导的他汀类药物作用的理解的提高可能有助于确定新的治疗靶点和策略。
