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Am. J. Respir. Cell Mol. Biol., Volume 19, Number 1, July, 1998 129-142

Prolonged Cell-cycle Arrest Associated with Altered cdc2 Kinase in Monocrotaline Pyrrole-treated Pulmonary Artery Endothelial Cells

Heath C. Thomas,* Michael W. Lamé, Dexter Morin, Dennis W. Wilson, and H. J. Segall

Departments of Veterinary: Pathology, Microbiology and Immunology, and Molecular Biosciences, University of California at Davis, Davis, California

Monocrotaline pyrrole (MCTP), a metabolite of the pyrrolizidine alkaloid monocrotaline, is thought to initiate damage to pulmonary endothelial cells resulting in delayed but progressive pulmonary interstitial edema, vascular wall remodeling, and increasing pulmonary hypertension. MCTP was previously shown to inhibit pulmonary endothelial cell proliferation and cause cell-cycle arrest in vitro. To determine the persistence of arrest and better characterize the cell-cycle stage at which it occurs, bovine pulmonary artery endothelial cells (BPAEC) under differing growth conditions were exposed to low (5 µg/ml) or high (34.5 µg/ml) concentrations of MCTP for varying times. Flow cytometric cell-cycle analysis was coupled with Western blot and biochemical analysis of cdc2 kinase and measurements of cell size. MCTP treatment induced a G2 + M phase arrest in 48-h exposed confluent BPAEC that persisted for at least 28 d and was associated with continued cellular enlargement. A short-duration MCTP exposure of confluent (low and high concentration) and log phase (high concentration) BPAEC caused persistent cell-cycle arrest for 1 wk, whereas a low-concentration exposure in log phase cells resulted in cell-cycle arrest with reversal 96 h after exposure. Western blot examination revealed that by 24 h of MCTP exposure, the phosphorylation state of cdc2 was consistent with the inactive form of the kinase (confirmed by biochemical assay); this alteration persisted through at least 96 h of exposure. We conclude that MCTP induces a progressive irreversible endothelial cell dysfunction leading to inactivation of cdc2 kinase and irreversible cell-cycle arrest at the G2 checkpoint.

* Present address: Department of Toxicology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., P.O. Box 1539, King of Prussia, PA 19406.
* %BAD is defined as the proportion of events in a histogram between the lowest G1 and the highest G2 that are due to debris and aggregates as modeled by the analysis program (MULTICYCLE manual).




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Copyright © 1998 American Thoracic Society.