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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number9556
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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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

Cite this

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.

In: Scientific Reports, Vol. 7, No. 1, 9556, 01.12.2017.

Research output: Contribution to journalArticle

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. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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