Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Mar 21;92(5):501-9.
doi: 10.1161/01.RES.0000061180.03813.0F. Epub 2003 Feb 13.

Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway

Affiliations
Free article

Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway

Brian W Fouty et al. Circ Res. .
Free article

Abstract

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 p27Kip1 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 G1 arrest and decreased DNA synthesis in rat PASMCs and did so in association with an increase in both total and cyclin E-bound p27Kip1. This caused a marked decrease in cyclin E kinase activity, which suggests an important role for p27Kip1 in the ability of mevastatin to induce G1 arrest. However, in PASMCs lacking functional p27Kip1, mevastatin still decreased cyclin E kinase activity, caused G1 arrest, and decreased DNA synthesis. In p27Kip1-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 p27Kip1-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 p27Kip1-independent pathways and may be important therapeutic agents in pulmonary arterial hypertension.

PubMed Disclaimer

Publication types

MeSH terms

LinkOut - more resources