Subscribe to RSS
Pharmacological properties of YM-254890, a specific Gαq/11 inhibitor, on thrombosis and neointima formation in mice
29 September 2004
Accepted after resubmission 23 April 2005
05 December 2017 (online)
The pharmacological properties of YM-254890,a specific Gαq/11 inhibitor, on acute thrombosis and chronic neointima formation after vascular injury have been investigated. FeCl3 was used to induce vascular injury in the carotid artery of mice. For the thrombosis studies, the test drug was either intravenously or orally administered before vascular injury. For the neointima studies, the test drug was orally administered 1 h before and twice daily for 1 week after vascular injury. Histological analysis was then performed 3 weeks later. YM-254890 significantly inhibited ex vivo platelet aggregation 5 min after intravenous bolus injection at 0.03 mg/kg or more, and 1 h after oral administration at 1 mg/kg. YM-254890 significantly inhibited thrombus formation after intravenous bolus injection at 0.03 mg/kg as well as after oral administration at 1 mg/kg, but tail transection bleeding time was significantly prolonged at 0.1 mg/kg for intravenous injection and 3 mg/kg for oral administration. Furthermore, oral administration of YM-254890 dose-dependently inhibited neointima formation 3 weeks after vascular injury with significant effects at 1 mg/kg twice daily for 1 week. Clopidogrel also significantly inhibited neointima formation at its antithrombotic dose, but its inhibitory potency was less than that of YM-254890. However, YM-254890 significantly reduced systemic blood pressure at doses 3 times higher than those that produced significant inhibitory effects on thrombosis and neointima formation. Though the systemic use of YM-254890 may be limited, owing to its narrow therapeutic window, this unique compound is a useful research tool for investigating the physiological roles of Gαq/11.
- 1 Goldschmidt PJ, Lopes N, Crawford LE. Atherosclerosis and coronary artery diseases. In Platelets. Michelson AD. editor. California, Elsevier/USA: 2002: 375-98.
- 2 Birnbaumer L. Receptor-to-effector signaling through G proteins: roles for beta gamma dimers as well as alpha subunits. Cell 1992; 71: 1069-72.
- 3 Clapham DE, Neer EJ. New roles for G-protein beta gamma-dimers in transmembrane signalling. Nature 1993; 365: 403-6.
- 4 Nurden P. et al. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb- IIIa complex function. J Clin Invest 1995; 95: 1612-22.
- 5 Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol 1999; 19: 2281-5.
- 6 Savi P, Labouret C, Delesque N. et al. P2y(12), a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Commun 2001; 283: 379-83.
- 7 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-72.
- 8 Moers A, Nieswandt B, Massberg S. et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med 2003; 9: 1418-22.
- 9 Gabbeta J, Yang X, Kowalska MA. et al. Platelet signal transduction defect with Gα subunit dysfunction and diminished Gαq in a patient with abnormal platelet responses. Proc Natl Acad Sci USA 1997; 94: 8750-5.
- 10 Offermanns S. et al. Defective platelet activation in Gαq-deficient mice. Nature 1997; 389: 183-6.
- 11 Taniguchi M, Nagai K, Arao N. et al. YM-254890, a novel platelet aggregation inhibitor produced by Chromobacterium sp. QS3666. J Antibiot 2003; 15: 358-63.
- 12 Kawasaki T, Taniguchi M, Moritani Y. et al. Antithrombotic and thrombolytic efficacy ofYM-254890, a Gq/11 inhibitor, in a rat model of arterial thrombosis. Thromb Haemost 2003; 90: 406-13.
- 13 Takasaki J. et al. YM-254890 is a novel selective Gαq/11 inhibitor. J Biol Chem 2004; 279: 47438-45.
- 14 Fay WP, Parker AC, Ansari MN. et al. Vitronectin inhibits the thrombotic response to arterial injury in mice. Blood 1999; 93: 1825-30.
- 15 Foster CJ, Prosser DM, Agans JM. et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001; 107: 1591-8.
- 16 Fisher-Dzoga K. et al. Ultrastructural and immunohistochemical studies of primary cultures of aortic medial cells. Exp Mol Pathol 1973; 18: 162-76.
- 17 Milligan G, Mullaney I, McCallum JF. Distribution and relative levels of expression of the phosphoinositidase- C-linked G-proteins Gαq and Gα11: absence of Gα11 in human platelets and haemopoietically derived cell lines. Biochim Biophys Acta 1993; 1179: 208-12.
- 18 Offermanns S. et al. Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Gαq. Proc Natl Acad Sci USA 1997; 94: 14089-94.
- 19 Farrehi PM, Ozaki CK, Carmeliet P. et al. Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation 1998; 97: 1002-8.
- 20 Krotz F, Sohn HY, Pohl U. Reactive oxygen species: players in the platelet game. Arterioscler Thromb Vasc Biol 2004; 24: 1988-96.
- 21 Iwatsuki Y, Kawasaki T, Hayashi K. et al. Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice. Thromb Haemost 2004; 92: 1221-8.
- 22 Carmeliet P, Moons L, Stassen JM. et al. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am J Pathol 1997; 150: 761-76.
- 23 Konstantinides S, Schafer K, Thinnes T. et al. Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice. Circulation 2001; 103: 576-83.
- 24 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
- 25 Haunstetter A, Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res 1998; 82: 1111-29.
- 26 Tanski WJ, Roztocil E, Hemady EA. et al. Role of Gαq in smooth muscle cell proliferation. J Vasc Surg 2004; 39: 639-44.
- 27 Keys JR, Greene EA, Koch WJ. et al. Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature. Hypertension 2002; 40: 660-6.