AMPK alpha 2 subunit is involved in platelet signaling, clot retraction, and thrombus stability

作者：Randriamboavonjy Voahanginirina; Isaak Johann; Froemel Timo; Viollet Benoit; Fisslthaler Beate; Preissner Klaus T; Fleming Ingrid^*

来源：Blood, 2010, 116(12): 2134-2140.

DOI：10.1182/blood-2010-04-279612

The adenosine monophosphate (AMP)activated protein kinase (AMPK) is a regulator of energy balance at the cellular and whole-body levels, but little is known about the role of AMPK in platelet activation. We report that both the alpha 1 and alpha 2 AMPK isoforms are expressed by human and murine platelets and that thrombin elicits the phosphorylation of AMPK alpha as well as the upstream kinase, liver kinase B1 (LKB1). In human platelets, the kinase inhibitors iodotubercidin and compound C significantly inhibited thrombin-induced platelet aggregation and clot retraction without affecting the initial increase in [Ca(2+)](i). Clot retraction was also impaired in platelets from AMPK alpha 2(-/-) mice but not from wild-type littermates or AMPK alpha 1(-/-) mice. Moreover, rebleeding was more frequent in AMPK alpha 2(-/-) mice, and the FeCl(3)-induced thrombi formed in AMPK alpha 2(-/-) mice were unstable. Mechanistically, AMPK alpha 2 was found to phosphorylate in vitro the Src-family kinase, Fyn, and isoform deletion resulted in the attenuated threonine phosphorylation of Fyn as well as the subsequent tyrosine phosphorylation of its substrate, beta 3 integrin. These data indicate that AMPK alpha 2-by affecting Fyn phosphorylation and activity-plays a key role in platelet alpha IIb beta 3 integrin signaling, leading to clot retraction and thrombus stability. (Blood. 2010;116(12):2134-2140)

• 出版日期2010-9-23