A novel ruthenium (II)-derived organometallic compound, TQ-6, potently inhibits platelet aggregation: Ex vivo and in vivo studies

Chih Hsuan Hsia, Marappan Velusamy, Joen Rong Sheu, Themmila Khamrang, Thanasekaran Jayakumar, Wan Jung Lu, Kuan Hung Lin, Chao Chien Chang

研究成果: 雜誌貢獻文章

3 引文 (Scopus)

摘要

Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 μM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β3 phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αIIbβ3-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.
原文英語
文章編號9556
期刊Scientific Reports
7
發行號1
DOIs
出版狀態已發佈 - 十二月 1 2017

指紋

Organometallic Compounds
Ruthenium
Fluorescein-5-isothiocyanate
Platelet Aggregation
Blood Platelets
Phosphorylation
Integrins
Bleeding Time
P-Selectin
Fibrinolytic Agents
Phospholipases
Cyclic Nucleotides
Platelet Aggregation Inhibitors
Platelet Activation
Mitogen-Activated Protein Kinases
Hydroxyl Radical
Fibrinogen
Protein Kinase C
Thrombosis
Cardiovascular Diseases

ASJC Scopus subject areas

  • General

引用此文

A novel ruthenium (II)-derived organometallic compound, TQ-6, potently inhibits platelet aggregation : Ex vivo and in vivo studies. / Hsia, Chih Hsuan; Velusamy, Marappan; Sheu, Joen Rong; Khamrang, Themmila; Jayakumar, Thanasekaran; Lu, Wan Jung; Lin, Kuan Hung; Chang, Chao Chien.

於: Scientific Reports, 卷 7, 編號 1, 9556, 01.12.2017.

研究成果: 雜誌貢獻文章

Hsia, Chih Hsuan ; Velusamy, Marappan ; Sheu, Joen Rong ; Khamrang, Themmila ; Jayakumar, Thanasekaran ; Lu, Wan Jung ; Lin, Kuan Hung ; Chang, Chao Chien. / A novel ruthenium (II)-derived organometallic compound, TQ-6, potently inhibits platelet aggregation : Ex vivo and in vivo studies. 於: Scientific Reports. 2017 ; 卷 7, 編號 1.
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abstract = "Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 μM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β3 phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αIIbβ3-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.",
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AU - Sheu, Joen Rong

AU - Khamrang, Themmila

AU - Jayakumar, Thanasekaran

AU - Lu, Wan Jung

AU - Lin, Kuan Hung

AU - Chang, Chao Chien

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AB - Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 μM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β3 phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αIIbβ3-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.

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