Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEMO, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3(-/-)) mice were developed to elucidate the platelet-related function(s) of MEMO. We found that agonist-induced aggregation and degranulation were reduced in MEKK3(-/-) platelets in vitro. MEMO deficiency significantly impaired integrin alpha IIb beta 3-mediated inside-out signaling but did not affect the outside-in signaling. At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3(-/-) mice showed delayed thrombus formation following FeCl3-induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3(-/-) mice. Moreover, MEKK3(-/-) mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI. These results suggest that MEMO plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.