Division of Cardiovascular Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, campus Gasthuisberg, Leuven, Belgium.
Nat Rev Cardiol. 2022 Oct;19(10):668-683. doi: 10.1038/s41569-022-00685-x. Epub 2022 Mar 30.
Sirtuins are NAD-dependent deacetylase and deacylase enzymes that control important cellular processes, including DNA damage repair, cellular metabolism, mitochondrial function and inflammation. Consequently, mammalian sirtuins are regarded as crucial regulators of cellular function and organism healthspan. Sirtuin activity and NAD levels decrease with age in many tissues, and reduced sirtuin expression is associated with several cardiovascular diseases. By contrast, increased sirtuin expression and activity slows disease progression and improves cardiovascular function in preclinical models and delays various features of cellular ageing. The potential cardiometabolic benefits of sirtuins have resulted in clinical trials with sirtuin-modulating agents; although expectations are high, these drugs have not yet been proven to improve healthspan. In this Review, we examine the role of sirtuins in atherosclerosis, summarize advances in the development of compounds that activate or inhibit sirtuin activity and critically evaluate the therapeutic potential of these agents.
Sirtuins 是 NAD 依赖性去乙酰化酶和去酰胺酶，可控制包括 DNA 损伤修复、细胞代谢、线粒体功能和炎症在内的重要细胞过程。因此，哺乳动物的 Sirtuins 被认为是细胞功能和生物体健康寿命的关键调节因子。在许多组织中，Sirtuins 的活性和 NAD 水平随年龄增长而降低，而 Sirtuins 表达的降低与几种心血管疾病有关。相比之下，在临床前模型中，增加 Sirtuins 的表达和活性可减缓疾病的进展并改善心血管功能，并延缓细胞衰老的各个方面。Sirtuins 的潜在心脏代谢益处导致了使用 Sirtuins 调节因子的临床试验；尽管期望很高，但这些药物尚未被证明能改善健康寿命。在这篇综述中，我们研究了 Sirtuins 在动脉粥样硬化中的作用，总结了激活或抑制 Sirtuins 活性的化合物的发展进展，并批判性地评估了这些药物的治疗潜力。
