Protein kinase A determines platelet life span and survival by regulating apoptosis.
J Clin Invest
; 127(12): 4338-4351, 2017 12 01.
Article
en En
| MEDLINE
| ID: mdl-29083324
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_endocrine_disorders
/
6_other_blood_disorders
Asunto principal:
Plaquetas
/
Apoptosis
/
Proteínas Quinasas Dependientes de AMP Cíclico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Clin Invest
Año:
2017
Tipo del documento:
Article
País de afiliación:
China