Department of Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Curr Atheroscler Rep. 2023 Dec;25(12):931-937. doi: 10.1007/s11883-023-01162-7. Epub 2023 Nov 18.
The focus of this article is to highlight the importance of the small GTPase, Ras-associated protein 1 (Rap1), in proprotein convertase subtilisin/kexin type 9 (PCSK9) regulation and atherosclerosis and type 2 diabetes etiology and discuss the potential therapeutic implications of targeting Rap1 in these disease areas.
Cardiometabolic disease characterized by obesity, glucose intolerance, dyslipidemia, and atherosclerotic cardiovascular disease remain an important cause of mortality. Evidence using mouse models of obesity and insulin resistance indicates that Rap1 deficiency increases proatherogenic PCSK9 and low-density lipoprotein cholesterol levels and predisposes these mice to develop obesity- and statin-induced hyperglycemia, which highlights Rap1's role in cardiometabolic dysfunction. Rap1 may also contribute to cardiovascular disease through its effects on vascular wall cells involved in the atherosclerosis progression. Rap1 activation, specifically in the liver, could be beneficial in the prevention of cardiometabolic perturbations, including type 2 diabetes, hypercholesterolemia, and atherosclerosis.
本文重点强调了小分子 GTP 酶 Ras 相关蛋白 1（Rap1）在蛋白水解酶原转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）调节、动脉粥样硬化和 2 型糖尿病发病机制中的重要性，并讨论了针对这些疾病领域的 Rap1 的潜在治疗意义。
以肥胖、葡萄糖耐量异常、血脂异常和动脉粥样硬化性心血管疾病为特征的心脏代谢疾病仍然是导致死亡的重要原因。使用肥胖和胰岛素抵抗的小鼠模型的证据表明，Rap1 缺乏会增加致动脉粥样硬化性 PCSK9 和低密度脂蛋白胆固醇水平，并使这些小鼠易发生肥胖和他汀类药物诱导的高血糖，这突出了 Rap1 在心脏代谢功能障碍中的作用。Rap1 还可能通过其对参与动脉粥样硬化进展的血管壁细胞的影响而导致心血管疾病。Rap1 的激活，特别是在肝脏中，可能有助于预防心脏代谢紊乱，包括 2 型糖尿病、高胆固醇血症和动脉粥样硬化。
