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Mevastatin Can Cause G₁ Arrest and Induce Apoptosis in Pulmonary Artery Smooth Muscle Cells Through a p27^Kip1-Independent Pathway

From the Division of Pulmonary Sciences and Critical Care Medicine (B.W.F., D.M.R.) and Department of Physiology and Biophysics (D.M.R.), University of Colorado Health Sciences Center, Denver, Colo.

Correspondence to Dr Brian Fouty, Box c272, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262. E-mail brian.fouty{at}uchsc.edu

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 G₁ 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 p27^Kip1 in the ability of mevastatin to induce G₁ arrest. However, in PASMCs lacking functional p27^Kip1, mevastatin still decreased cyclin E kinase activity, caused G₁ 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.

Key Words: vascular smooth muscle • pulmonary hypertension • p27^Kip1 • HMG-CoA reductase

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