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Protein kinase A determines platelet life span and survival by regulating apoptosis.

ABSTRACT: 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.

SUBMITTER: Zhao L

PROVIDER: S-EPMC5707139 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Protein kinase A determines platelet life span and survival by regulating apoptosis.

Zhao Lili L Liu Jun J He Chunyan C Yan Rong R Zhou Kangxi K Cui Qingya Q Meng Xingjun X Li Xiaodong X Zhang Yang Y Nie Yumei Y Zhang Yang Y Hu Renping R Liu Yancai Y Zhao Lian L Chen Mengxing M Xiao Weiling W Tian Jingluan J Zhao Yunxiao Y Cao Lijuan L Zhou Ling L Lin Anning A Ruan Changgeng C Dai Kesheng K

The Journal of clinical investigation 20171030 12

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 fro ...[more]

PMID: 29083324

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Project description:Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue damage. The lung is particularly susceptible to systemic inflammation, leading to acute lung injury. Key to inflammation-induced lung damage is the excessive migration of neutrophils across the vascular endothelium. The mechanisms which regulate neutrophil activation and migration in sepsis are not well defined but there is growing evidence that platelets are actively involved and play a key role in microvascular permeability and neutrophil-mediated organ damage. We previously identified PKC-delta (PKC?) as a critical regulator of the inflammatory response in sepsis and demonstrated PKC? inhibition was lung protective. However, the role of PKC? in sepsis-induced platelet activation and platelet-leukocyte interactions is not known. In this study, rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Following surgeries, a PKC? inhibitor (200?g/kg) or vehicle (PBS) was administered intra-tracheally. At 24 hours post-surgeries, lung tissue, BAL fluid, and blood samples were collected. While sepsis caused thrombocytopenia, the remaining circulating platelets were activated as demonstrated by increased p-selectin expression, elevated plasma PF4, and enhanced platelet-leukocyte aggregate formation compared to Sham animals. Platelet activation was associated with increased platelet PKC? activity. Inhibition of PKC? attenuated sepsis-induced platelet activation, secretion and aggregate formation. Sepsis-induced thrombocytopenia was also significantly reduced and circulating platelet numbers were similar to sham animals. In the lung, sepsis induced significant influx of platelets and neutrophils and the development of lung injury. Administration of the PKC? inhibitor decreased platelet and neutrophil influx, and was lung protective. Thus, PKC? inhibition modulated platelet activity both locally and systemically, decreased neutrophil influx into the lung, and was lung protective. We demonstrate for the first time that PKC? plays an important role in platelet activation and platelet-neutrophil interaction during sepsis.

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Protein kinase A determines platelet life span and survival by regulating apoptosis.

Publications

Protein kinase A determines platelet life span and survival by regulating apoptosis.

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