期刊
CIRCULATION RESEARCH
卷 92, 期 5, 页码 501-509出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000061180.03813.0F
关键词
vascular smooth muscle; pulmonary hypertension; p27(Kip1); HMG-CoA reductase
资金
- NHLBI NIH HHS [P01 HL 14985-29, R01 HL57282-03, HL48038-09] Funding Source: Medline
Advanced pulmonary arterial hypertension is characterized by extensive vascular remodeling that is usually resistant to vasodilator therapy. Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting step for cholesterol synthesis. HMG-CoA reductase inhibitors have been shown to upregulate the cyclin-dependent kinase inhibitor p27(Kip1) and to block cell proliferation through cholesterol-independent pathways. The aim of this study was to determine the effect of mevastatin on DNA synthesis, cell cycle progression, and cell proliferation in rat pulmonary artery smooth muscle cells ( PASMCs). We found that mevastatin induced G(1) arrest and decreased DNA synthesis in rat PASMCs and did so in association with an increase in both total and cyclin E-bound p27(Kip1). This caused a marked decrease in cyclin E kinase activity, which suggests an important role for p27Kip1 in the ability of mevastatin to induce G(1) arrest. However, in PASMCs lacking functional p27(Kip1), mevastatin still decreased cyclin E kinase activity, caused G(1) arrest, and decreased DNA synthesis. In p27(Kip1)-deficient PASMCs, mevastatin induced a greater reduction of cyclin E protein levels ( to 35% of control) than in wild-type cells ( to 70% of control) and also reduced the phosphorylation of cdk2 on threonine 160. Mevastatin also caused apoptosis in both wild-type and p27(Kip1)-deficient PASMCs and was able to do so at a dose that did not induce cell cycle arrest. These data suggest that HMG-CoA reductase inhibitors can both inhibit cell proliferation and induce apoptosis in PASMCs through p27(Kip1)-independent pathways and may be important therapeutic agents in pulmonary arterial hypertension.
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