Protein kinase A determines platelet life span and survival by regulating apoptosis
Protein kinase A determines platelet life span and survival by regulating apoptosis
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蛋白激酶 A 通过调节细胞凋亡来决定血小板寿命和存活率
DOI：
10.1172/jci95109
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Dai K
中科院分区：
文献类型：
--
作者：
Zhao L;Liu J;He C;Yan R;Zhou K;Cui Q;Meng X;Li X;Zhang Y;Nie Y;Zhang Y;Hu R;Liu Y;Zhao L;Chen M;Xiao W;Tian J;Zhao Y;Cao L;Zhou L;Lin A;Ruan C;Dai K
细胞凋亡限制了血小板在循环中的寿命，并导致储存损伤，严重限制了储存的血小板的保质期。此外，越来越多的证据表明，在许多常见疾病中，各种病理刺激引起的血小板凋亡会导致血小板减少。然而，关于血小板凋亡是如何启动或调节的，人们知之甚少。在这里，我们发现在体外老化的血小板、储存的血小板以及免疫性血小板减少症(ITP)、糖尿病和细菌感染患者的血小板中，PKA活性显著降低。抑制或基因消融PKA在体外可引起内源性程序性血小板凋亡，在体内可迅速清除血小板。抑制PKA导致促凋亡蛋白BAD在Ser155处去磷酸化，导致促凋亡蛋白bclxl在线粒体中的滞留，从而导致随后的细胞凋亡。值得注意的是，在正常小鼠和ITP小鼠模型中，PKA的激活保护了保存或病理刺激诱导的血小板的凋亡，并提高了外周血小板水平。因此，这些发现确认PKA是决定血小板寿命和存活率的血小板凋亡的动态平衡调节因子。此外，这些结果表明，调节PKA活性是延长血小板货架期的一种有前途的策略，并对治疗与血小板数量相关的疾病和疾病具有深远的意义。
Apoptosis delimits platelet life span in the circulation and leads to storage lesion, which severely limits the shelf life of stored platelets. Moreover, accumulating evidence indicates that platelet apoptosis provoked by various pathological stimuli results in thrombocytopenia in many common diseases. However, little is known about how platelet apoptosis is initiated or regulated. Here, we show that PKA activity is markedly reduced in platelets aged in vitro, stored platelets, and platelets from patients with immune thrombocytopenia (ITP), diabetes, and bacterial infections. Inhibition or genetic ablation of PKA provoked intrinsic programmed platelet apoptosis in vitro and rapid platelet clearance in vivo. PKA inhibition resulted in dephosphorylation of the proapoptotic protein BAD at Ser155, resulting in sequestration of prosurvival protein BCL-XL in mitochondria and subsequent apoptosis. Notably, PKA activation protected platelets from apoptosis induced by storage or pathological stimuli and elevated peripheral platelet levels in normal mice and in a murine model of ITP. Therefore, these findings identify PKA as a homeostatic regulator of platelet apoptosis that determines platelet life span and survival. Furthermore, these results suggest that regulation of PKA activity represents a promising strategy for extending platelet shelf life and has profound implications for the treatment of platelet number-related diseases and disorders.