Kayzuka Cezar, Rondon-Pereira Vitória Carolina, Nogueira Tavares Cecilia, Pacheco Pachado Mayra, Monica Fabiola Zakia, Tanus-Santos Jose Eduardo, Lacchini Riccardo
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil.
Expert Opin Drug Metab Toxicol. 2025 Jun;21(6):689-701. doi: 10.1080/17425255.2025.2491732. Epub 2025 Apr 17.
Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear.
This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024.
The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.
他汀类药物通过降低血清胆固醇水平显著降低了心血管疾病的死亡率。除了其降脂作用外，他汀类药物还可改善血管功能、减轻炎症、减少活性氧（ROS）生成并稳定动脉粥样硬化斑块。然而，这些多效性作用的潜在机制仍不清楚。
本叙述性综述总结并讨论了可能解释他汀类药物部分多效性作用的表观遗传机制。这种方法有助于重新评估他汀类药物的使用，而不仅仅局限于其降低胆固醇的益处。使用特定检索词在PubMed和Scopus数据库中进行了结构化检索，检索截至2024年8月发表的文章。
他汀类药物的多效性作用，包括那些由类异戊二烯途径介导的作用，部分解释了它们的临床益处。通过抑制组蛋白脱乙酰酶（HDACs，即“橡皮擦”）和DNA甲基转移酶（DNMTs，即“书写者”），他汀类药物促进基因启动子区域组蛋白乙酰化增加和DNA甲基化减少。这些表观遗传修饰增强了染色质的可及性，促进基因转录并保护心血管系统。对这些表观遗传机制的进一步研究可能支持他汀类药物重新定位以用于更广泛的治疗应用。他汀类药物的益处可能超出其在管理高胆固醇血症方面的作用，因为它们的多效性作用通过独立于降低低密度脂蛋白胆固醇的机制有助于预防心血管疾病相关的死亡率。
