King's College London School of Medicine, London SE1 7GL, United Kingdom.
Cytokine Growth Factor Rev. 2011 Jun;22(3):167-75. doi: 10.1016/j.cytogfr.2011.05.004. Epub 2011 Jun 22.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are a drug class that reduce the level of cholesterol in the blood. As a result, statins are used to suppress the progression of cardiovascular disease. Evidence points to another component of statins involving the non-lipid effects of the drug class in preventing cardiovascular disease. One specific mediator of this action is the transforming growth factor β (TGF-β) superfamily. The TGF-β superfamily consists of proteins that include TGF-β and bone morphogenetic proteins (BMPs). These proteins regulate cellular pathways to mediate effects including immunomodulation, cell cycling, and angiogenesis. One pathway that mediates these effects is Ras. Moreover, within this pathway, different functions are possible depending on the activation of the specific receptor subtype. This review discusses the recent development of the non-lipid effects of statins in preventing cardiovascular disease progression by regulating Ras pathway of the TGF-β superfamily, especially RhoA/ROCK pathway.
A systematic PubMed database search of all English-language articles up to 2011 was conducted using the following terms: statin, TGF-β, Ras, ROCK, GGPP, inducible nitric oxide synthase, endothelial nitric oxide synthase, actin filament formation, PPARγ, MMP-2, and human trials.
With better understanding of the pathway, various mediators were identified; some of these mediators are important biomarkers producing more specific and accurate assessment of the pleiotropic effects of statins. The review of human trials also highlights that more specific biomarkers are employed in recent studies, and the non-lipid effects on human subjects are more accurately documented. Confirmation of the accuracy of these biomarkers by further large-scale studies and further development of new biomarkers may prove an important path leading to better patient selection for treatment, and thus better cost-effectiveness may be achieved.
3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂，又称他汀类药物，是一类降低血液中胆固醇水平的药物。因此，他汀类药物被用于抑制心血管疾病的进展。有证据表明，他汀类药物的另一个作用成分涉及该药物类别的非脂类效应，可预防心血管疾病。这种作用的一个特定介质是转化生长因子β（TGF-β）超家族。TGF-β 超家族由包括 TGF-β和骨形态发生蛋白（BMPs）在内的蛋白质组成。这些蛋白质调节细胞途径，介导包括免疫调节、细胞周期和血管生成在内的效应。介导这些效应的一条途径是 Ras。此外，在这条途径中，不同的功能可能取决于特定受体亚型的激活。本综述讨论了他汀类药物通过调节 TGF-β 超家族的 Ras 途径，特别是 RhoA/ROCK 途径，预防心血管疾病进展的非脂类效应的最新进展，特别是 RhoA/ROCK 途径。
使用以下术语对截至 2011 年的所有英文文献进行了系统的 PubMed 数据库检索：他汀类药物、TGF-β、Ras、ROCK、GGPP、诱导型一氧化氮合酶、内皮型一氧化氮合酶、肌动蛋白丝形成、PPARγ、MMP-2 和人体试验。
随着对途径的更好理解，确定了各种介质；其中一些介质是重要的生物标志物，可更具体和准确地评估他汀类药物的多效性。人体试验的综述还强调，最近的研究中使用了更具体的生物标志物，并且更准确地记录了他汀类药物对人体的非脂类作用。通过进一步的大规模研究确认这些生物标志物的准确性，并进一步开发新的生物标志物，可能证明是改善患者选择治疗的重要途径，从而实现更好的成本效益。
