State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
J Thromb Haemost. 2023 Feb;21(2):344-358. doi: 10.1016/j.jtha.2022.11.018. Epub 2022 Dec 22.
Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the underlying mechanism is still not well-illustrated, and the therapeutic targets and candidates are even less.
In order to investigate the mechanisms for platelet shedding after vasopressin treatment and find new therapeutic targets for thrombocytopenia.
Platelet production was evaluated both in vivo and in vitro after arginine vasopressin (AVP) administration. The underlying biological mechanism of AVP-triggered thrombopoiesis were then investigated by a series of molecular and bioinformatics techniques.
it is observed that proplatelet formation and platelet shedding in the final stages of thrombopoiesis promoted by AVP, an endogenous hormone, can quickly increases peripheral platelets. This rapid elevation is thus able to speed up platelet recovery after radiation as expected. The mechanism analysis reveal that proplatelet formation and platelet release from mature MKs facilitated by AVP is mainly mediated by Akt-regulated mitochondrial metabolism. In particular, phosphorylated Akt regulates mitochondrial metabolism through driving the association of hexokinase-2 with mitochondrial voltage dependent anion channel-1 in AVP-mediated thrombopoiesis. Further studies suggest that this interaction is stabilized by IκBα, the expression of which is controlled by insulin-regulated membrane aminopeptidase.
these data demonstrate that phosphorylated Akt-mediated mitochondrial metabolism regulates platelet shedding from MKs in response to AVP, which will provide new therapeutic targets and further drug discovery clues for thrombocytopenia treatment.
在血小板生成中，成熟巨核细胞（MK）的血小板脱落是快速有效提高循环血小板的关键步骤，然而，其潜在机制仍未得到充分说明，治疗靶点和候选药物就更少了。
为了研究血管加压素（AVP）治疗后血小板脱落的机制，并为血小板减少症寻找新的治疗靶点。
在给予精氨酸血管加压素（AVP）后，在体内和体外评估血小板的生成。然后，通过一系列分子和生物信息学技术研究 AVP 触发的造血的潜在生物学机制。
观察到，作为内源性激素的 AVP 促进了血小板生成的最后阶段的原血小板形成和血小板脱落，能够迅速增加外周血小板。这种快速升高能够如预期的那样加速辐射后的血小板恢复。机制分析表明，AVP 介导的原血小板形成和成熟 MK 中的血小板释放主要是由 Akt 调节的线粒体代谢介导的。特别是，磷酸化 Akt 通过驱动己糖激酶-2 与 AVP 介导的造血中线粒体电压依赖性阴离子通道-1 的结合来调节线粒体代谢。进一步的研究表明，这种相互作用通过胰岛素调节的膜氨肽酶控制的 IκBα 的表达来稳定。
这些数据表明，磷酸化 Akt 介导的线粒体代谢调节了 MK 中对 AVP 反应的血小板脱落，这将为血小板减少症的治疗提供新的治疗靶点和进一步的药物发现线索。
