Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21Cip1.
OBJECTIVE
Obovatol is isolated from Magnolia obovata leaves and this active component has various pharmacological properties such as anti-oxidant, anti-platelet, anti-fungal and anti-inflammatory activities. In the present study, we investigated the inhibitory effects of obovatol on in vitro vascular smooth muscle cell (VSMC) proliferation and in vivo neointimal formation in a rat carotid artery injury model.


RESULTS
Obovatol (1-5 microM) exerted concentration-dependent inhibition on platelet-derived growth factor (PDGF)-BB-induced rat VSMC proliferation, without exhibiting any cellular toxicity or apoptosis, as determined by cell count, [3H]thymidine incorporation and Annexin-V-binding analyses. Treatment with obovatol blocked the cell cycle in G1 phase by down-regulating the expression of cyclins and CDKs, and selectively up-regulating the expression of p21Cip1, a well-known CDK inhibitor. Effects of perivascular delivery of obovatol were assessed 14 days after injury. The angiographic mean luminal diameters of the obovatol-treated groups (100 microg and 1 mg: 0.78+/-0.06 and 0.77+/-0.07AU, respectively) were significantly larger than that of the control group (0.58+/-0.07AU). The obovatol-treated groups (100 microg and 1mg: 0.14+/-0.04 and 0.09+/-0.03 mm2, respectively) showed significant reduction in neointimal formation versus the control group (0.17+/-0.02 mm2). Immunohistochemical staining demonstrated strong expression of p21Cip1 in the neointima of the obovatol-treated groups.


CONCLUSIONS
These data suggest that obovatol inhibits VSMC proliferation by perturbing cell cycle progression, possibly due to activation of p21Cip1 pathway. These results also show that obovatol may have potential as an anti-proliferative agent for the treatment of restenosis and atherosclerosis.
Lim
Yong
Y
Research Institute of Veterinary Medicine, Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Kwon
Jin-Sook
JS
Kim
Dong-Woon
DW
Lee
Seung-Ho
SH
Park
Rho-Kwan
RK
Lee
Jung-Jin
JJ
Hong
Jin-Tae
JT
Yoo
Hwan-Soo
HS
Kwon
Byoung-Mog
BM
Yun
Yeo-Pyo
YP
D000818:Animals; D001011:Aorta / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D018450:Disease Progression; D031566:Magnolia / Q000378:metabolism*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology*
D001713:Biphenyl Compounds; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016376:Oligonucleotides, Antisense; D010647:Phenyl Ethers; D010936:Plant Extracts; C036795:obovatol