The novel compound MP407 inhibits platelet aggregation through cyclic AMP-dependent processes

Chung Shuen Lin, Tso Hsiao Chen, I. Hsin Lin, An Rong Lee, Tz Chong Chou

Research output: Contribution to journalArticle

Abstract

Platelet hyperactivity plays a critical role for initiating several vascular diseases such as atherothrombosis. Therefore, development of effective antiplatelet agents is necessary for ameliorating platelet-related diseases. In this study, we investigated the effects of the new synthesized compound, MP407 on platelet aggregation and further elucidated the underlying mechanisms. Our results demonstrated that MP407 dose-dependently inhibited collagen-induced platelet aggregation, thromboxane B2 (TXB2) production, intracellular Ca2+ mobilization, platelet membrane GPIIb/IIIa expression, and the phosphorylation of Akt, GSK3β, p38MAPK, and phospho (Ser) PKC substrate (p47). Moreover, MP407 is able to increase the cyclic AMP formation both in resting and activated platelets. However, blocking cyclic AMP formation with 2'5'-ddAdo, an inhibitor of adenylate cyclase, greatly reversed the antiplatelet activity of MP407 and related platelet-activating pathways. MP407 also enhanced VASP phosphorylation at Ser157 in collagen-stimulated platelets, which was attenuated by addition of 2'5'-ddAdo. Therefore, the antiplatelet activity of MP407 may be modulated by cyclic AMP-dependent regulation of Akt, GSK3β, p38MAPK and VASP phosphorylation. Notably, treatment with MP407 markedly reduced the pulmonary thrombosis and the numbers of paralysis and death in mice induced by ADP injection, but did not affect the bleeding time. Taken together, MP407 may be a potential candidate or lead compound for developing novel antiplatelet or antithrombotic agents for platelet hyperactivity-triggered disease therapy.

Original languageEnglish
JournalEuropean Journal of Pharmacology
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Platelet Aggregation
Cyclic AMP
Blood Platelets
Platelet Aggregation Inhibitors
Phosphorylation
Collagen
Thromboxane B2
Bleeding Time
Fibrinolytic Agents
Vascular Diseases
Paralysis
Adenosine Diphosphate
Thrombosis
Lung
Injections
Membranes
Therapeutics

Keywords

  • Cyclic AMP
  • GSK3β
  • MP407
  • Platelet aggregation
  • Thromboxane B
  • VASP

ASJC Scopus subject areas

  • Pharmacology

Cite this

The novel compound MP407 inhibits platelet aggregation through cyclic AMP-dependent processes. / Lin, Chung Shuen; Chen, Tso Hsiao; Lin, I. Hsin; Lee, An Rong; Chou, Tz Chong.

In: European Journal of Pharmacology, 2017.

Research output: Contribution to journalArticle

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