Effects of KTJ740, a novel antithrombotic agent, on platelet-derived growth factor-induced rat aortic smooth muscle cell proliferation and cell cycle progression.
Hyperproliferation of platelet-derived growth factor (PDGF)-BB-induced vascular smooth muscle cell (VSMC) is a hallmark of atherosclerosis and related vascular disorders. In the previous study, we reported that KTJ740 [2-chloro-3-(4-(ethylcarboxy)-phenyl)-amino-1,4-naphthoquinone], a newly synthesized vitamin K derivative, has potent antithrombotic effects in mice and antiplatelet activity in vitro and ex vivo. In the present study, we have tested that KTJ740 could inhibit PDGF-BB-stimulated VSMC proliferation. We have examined the potential inhibitory effect of this compound on rat aortic smooth muscle cells (RASMCs). Our results show that this compound significantly inhibits PDGF-BB-stimulated RASMC number and DNA synthesis in a concentration-dependent manner. Furthermore, we have examined its effect on cell cycle progression by flow cytometry. KTJ740 treatment resulted in a significant arrest in cell cycle progression of RASMCs induced by PDGF-BB, and this effect was achieved by suppressing activation of PDGF-beta receptor (PDGF-Rbeta) tyrosine kinase pathway. These results suggest that a possibility of KTJ740 can be a potential agent to control vascular disorders and its antiproliferative mechanism may be mediated through PDGF-Rbeta tyrosine kinase-dependent signaling pathway.
Kim
Tack-Joong
TJ
College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University, Heungduk-Gu, Cheongju, Korea.
Jeon
Jinseon
J
Jin
Yong-Ri
YR
Son
Dong-Ju
DJ
Yoo
Hwan-Soo
HS
Hong
Jin-Tae
JT
Ryu
Chung-Kyu
CK
Shin
Hwa-Sup
HS
Lee
Kwang-Ho
KH
Yun
Yeo-Pyo
YP
D000704:Analysis of Variance; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology*; D000077214:Becaplermin; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005434:Flow Cytometry; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D051966:Phospholipase C gamma / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D005343:Fibrinolytic Agents; C523859:KTJ740; D009285:Naphthoquinones; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C099852:PDGF receptor tyrosine kinase; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma