Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China.
J Cell Mol Med. 2021 Apr;25(8):4124-4135. doi: 10.1111/jcmm.16382. Epub 2021 Feb 23.
Thrombocytopenia is independently related with increased mortality in severe septic patients. Renin-angiotensin system (RAS) is elevated in septic subjects; accumulating studies show that angiotensin II (Ang II) stimulate the intrinsic apoptosis pathway by promoting reactive oxygen species (ROS) production. However, the mechanisms underlying the relationship of platelet apoptosis and RAS system in sepsis have not been fully elucidated. The present study aimed to elucidate whether the RAS was involved in the pathogenesis of sepsis-associated thrombocytopenia and explore the underlying mechanisms. We found that elevated plasma Ang II was associated with decreased platelet count in both patients with sepsis and experimental animals exposed to lipopolysaccharide (LPS). Besides, Ang II treatment induced platelet apoptosis in a concentration-dependent manner in primary isolated platelets, which was blocked by angiotensin II type 1 receptor (AT1R) antagonist losartan, but not by angiotensin II type 2 receptor (AT2R) antagonist PD123319. Moreover, inhibiting AT1R by losartan attenuated LPS-induced platelet apoptosis and alleviated sepsis-associated thrombocytopenia. Furthermore, Ang II treatment induced oxidative stress level in a concentration-dependent manner in primary isolated platelets, which was partially reversed by the AT1R antagonist losartan. The present study demonstrated that elevated Ang II directly stimulated platelet apoptosis through promoting oxidative stress in an AT1R-dependent manner in sepsis-associated thrombocytopenia. The results would helpful for understanding the role of RAS system in sepsis-associated thrombocytopenia.
血小板减少症与严重脓毒症患者的死亡率增加独立相关。脓毒症患者的肾素-血管紧张素系统（RAS）升高；越来越多的研究表明，血管紧张素 II（Ang II）通过促进活性氧（ROS）的产生来刺激内在凋亡途径。然而，血小板凋亡与 RAS 系统在脓毒症中的关系的机制尚未完全阐明。本研究旨在阐明 RAS 是否参与脓毒症相关血小板减少症的发病机制，并探讨其潜在机制。我们发现，在脓毒症患者和暴露于脂多糖（LPS）的实验动物中，升高的血浆 Ang II 与血小板计数减少相关。此外，Ang II 以浓度依赖的方式在原代分离的血小板中诱导血小板凋亡，该作用被血管紧张素 II 型 1 受体（AT1R）拮抗剂氯沙坦阻断，但被血管紧张素 II 型 2 受体（AT2R）拮抗剂 PD123319 阻断。此外，氯沙坦通过抑制 AT1R 减轻 LPS 诱导的血小板凋亡并缓解脓毒症相关血小板减少症。此外，Ang II 以浓度依赖的方式在原代分离的血小板中诱导氧化应激水平增加，该作用部分被 AT1R 拮抗剂氯沙坦逆转。本研究表明，在脓毒症相关血小板减少症中，升高的 Ang II 通过促进 AT1R 依赖性氧化应激直接刺激血小板凋亡。这些结果有助于了解 RAS 系统在脓毒症相关血小板减少症中的作用。
