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A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

ABSTRACT: Naphthalimide derivatives have multiple biological activities, including antitumour and anti-inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. The data revealed that compound 5 (5-10 μM) inhibited collagen- and convulxin- but not thrombin- or U46619-mediated platelet aggregation, suggesting that compound 5 is more sensitive to the inhibition of glycoprotein VI (GPVI) signalling. Indeed, compound 5 could inhibit the phosphorylation of signalling molecules downstream of GPVI, followed by the inhibition of calcium mobilization, granule release and GPIIb/IIIa activation. Moreover, compound 5 prevented pulmonary embolism and prolonged the occlusion time, but tended to prolong the bleeding time, indicating that it can prevent thrombus formation but may increase bleeding risk. This study is the first to demonstrate that the naphthalimide derivative compound 5 exerts antiplatelet and antithrombotic effects. Future studies should modify compound 5 to synthesize more potent and efficient antiplatelet agents while minimizing bleeding risk, which may offer a therapeutic potential for cardiovascular diseases.

SUBMITTER: Shih TL

PROVIDER: S-EPMC8500964 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

Shih Tzenge-Lien TL Lin Kuan-Hung KH Chen Ray-Jade RJ Chen Ting-Yu TY Kao Wei-Ting WT Liu Jen-Wei JW Wang Hsueh-Hsiao HH Peng Hsien-Yu HY Sun Yu-Yo YY Lu Wan-Jung WJ

Journal of cellular and molecular medicine 20210827 19

Naphthalimide derivatives have multiple biological activities, including antitumour and anti-inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. ...[more]

PMID: 34448532

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Project description:BackgroundArterial thrombotic events are the leading causes of death worldwide, and the therapeutic effects of current antiplatelet drugs are not fully satisfactory. Oroxylin A (OroA), a flavone compound extracted from Scutellaria radix, possesses cardioprotective and many other pharmacological effects. While platelets play a crucial role in the development of myocardial infarction, the direct effects of OroA on platelet activation and thrombosis have yet to be investigated.MethodsFeCl₃-induced arteriole thrombosis and whole-blood perfusion were used to assess the inhibitory effect of OroA on thrombus formation. A myocardial ischemia model was employed to evaluate the protective effect of OroA on myocardial injury. Multiple platelet function studies including platelet aggregation, platelet spreading, clot retraction were performed. Network pharmacology, flow cytometry, enzyme-linked immunosorbent assay, co-immunoprecipitation and western blot were utilized to explore the mechanism of OroA on platelet activation.ResultsOroA inhibited thrombus formation with less bleeding risk compared with aspirin. OroA protected against myocardial injury by suppressing microvascular thrombosis and platelet infiltration. OroA suppressed different agonist-induced platelet activation in a concentration-dependent manner, showing greater antiplatelet activity against collagen-induced platelet aggregation compared to ADP or thrombin-induced aggregation. OroA decreased granule release, integrin αIIbβ3 activation, platelet spreading and clot retraction. As a flavone, OroA boosted superoxide dismutase (SOD) and glutathione (GSH) activities and decreased malondialdehyde (MDA), oxidized glutathione (GSSG) and ROS levels in platelets during oxidative stress. OroA binds to SHP-2 and prevents its oxidative inactivation, leading to the tyrosine dephosphorylation of Src, Syk and PLCγ2, as well as the reduction of Ca2+ influx and PKC phosphorylation in GPVI signaling.ConclusionsOroA inhibits platelet activation, thrombus formation and myocardial injury via reversing SHP-2 oxidative inactivation thereby attenuating collagen-induced GPVI signaling. With minor bleeding risk and no obvious pharmacological toxicity, OroA holds promising therapeutic potential as an antithrombotic drug.

Project description:Thrombosis, like other cardiovascular diseases, has a strong genetic component, with largely unknown determinants. EMILIN2, Elastin Microfibril Interface Located Protein2, was identified as a candidate gene for thrombosis in mouse and human quantitative trait loci studies. EMILIN2 is expressed during cardiovascular development, on cardiac stem cells, and in heart tissue in animal models of heart disease. In humans, the EMILIN2 gene is located on the short arm of Chromosome 18, and patients with partial and complete deletion of this chromosome region have cardiac malformations. To understand the basis for the thrombotic risk associated with EMILIN2, EMILIN2 deficient mice were generated. The findings of this study indicate that EMILIN2 influences platelet aggregation induced by adenosine diphosphate, collagen, and thrombin with both EMILIN2-deficient platelets and EMILIN2-deficient plasma contributing to the impaired aggregation response. Purified EMILIN2 added to platelets accelerated platelet aggregation and reduced clotting time when added to EMILIN2-deficient mouse and human plasma. Carotid occlusion time was 2-fold longer in mice with platelet-specific EMILIN2 deficiency, but stability of the clot was reduced in mice with both global EMILIN2 deficiency and with platelet-specific EMILIN2 deficiency. In vitro clot retraction was markedly decreased in EMILIN2 deficient mice, indicating that platelet outside-in signaling was dependent on EMILIN2. EMILIN1 deficient mice and EMILIN2:EMILIN1 double deficient mice had suppressed platelet aggregation and delayed clot retraction similar to EMILIN2 mice, but EMILIN2 and EMILIN1 had opposing affects on clot retraction, suggesting that EMILIN1 may attenuate the effects of EMILIN2 on platelet aggregation and thrombosis. In conclusion, these studies identify multiple influences of EMILIN2 in pathophysiology and suggest that its role as a prothrombotic risk factor may arise from its effects on platelet aggregation and platelet mediated clot retraction.

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A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

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A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

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