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Elevated angiotensin II induces platelet apoptosis through promoting oxidative stress in an AT1R-dependent manner during sepsis |
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| Authors: | Dun-Feng Xu Yu-Jian Liu Yan-Fei Mao Yan Wang Chu-Fan Xu Xiao-Yan Zhu Lai Jiang |
| Affiliation: | 1. 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 Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Software (equal), Writing - original draft (lead);2. School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China Contribution: Formal analysis (equal), Funding acquisition (equal), Methodology (equal);3. Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Contribution: Funding acquisition (equal), Investigation (equal);4. Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Contribution: Methodology (supporting);5. 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 Contribution: Methodology (supporting);6. Department of Physiology, Navy Medical University, Shanghai, China;7. Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China |
| Abstract: | 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. |
| Keywords: | angiotensin II (Ang II) angiotensin II receptor blocker (ARB) apoptosis platelet reactive oxygen species (ROS) thrombocytopenia |