β-Sitosterol inhibits cell cycle progression of rat aortic smooth muscle cells through increases of p21cip1 protein.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a central role in the pathogenesis of atherosclerosis. β-Sitosterol, an important phytosterol found in plant food, is known to exert antiatherosclerosis activity. However, the molecular mechanisms underlying β-sitosterol-induced antiproliferation of VSMCs were still not clear. This study demonstrated that β-sitosterol (1-20 μM) concentration-dependently inhibited proliferation of rat aortic smooth muscle cells (RASMCs) without cytotoxic effect. Flow cytometric analysis revealed that β-sitosterol arrested cell cycle progression through down-regulation of cyclin E and cyclin-dependent kinase (CDK)2 and up-regulation of p21cip1. In the β-sitosterol-treated RASMCs, the formation of the CDK2-p21cip1 complex was increased and the assayable CDK2 activity was decreased. Knockdown of the expression of p21cip1 gene prevented β-sitosterol-induced cell cycle arrest in RASMCs. In conclusion, β-sitosterol inhibited VSMC proliferation by increasing the levels of p21cip1 protein, which in turn inhibited the CDK2 activity, and finally interrupted the progress of the cell cycle.
Chien
Ming-Hsien
MH
Taipei Medical University-Wang-Fang Hospital, Taipei, Taiwan.
Lee
Tong-Sheng
TS
Liang
Yu-Chih
YC
Lee
Wen-Sen
WS
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012855:Sitosterols / Q000009:adverse effects / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000960:Hypolipidemic Agents; D012855:Sitosterols; C025473:gamma-sitosterol