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Blood, 1 February 2002, Vol. 99, No. 3, pp. 939-945
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Cyclin A transcriptional suppression is the major mechanism
mediating homocysteine-induced endothelial cell growth
inhibition
Hong Wang,
XiaoHua Jiang,
Fan Yang,
Gary B. Chapman,
William Durante,
Nicholas E. S. Sibinga, and
Andrew I. Schafer
From the Departments of Medicine and Pharmacology,
Baylor College of Medicine, Department of Bioengineering, Rice
University, and VA Medical Center, Houston, TX; and
Medicine/Cardiology, Albert Einstein College of Medicine, New York, NY.
Previously, it was reported that homocysteine (Hcy) specifically
inhibits the growth of endothelial cells (ECs), suppresses Ras/mitogen-activated protein (MAP) signaling, and arrests cell growth at the G1/S transition of the cell cycle. The
present study investigated the molecular mechanisms underlying this
cell-cycle effect. Results showed that clinically relevant
concentrations (50 µM) of Hcy significantly inhibited the expression
of cyclin A messenger RNA (mRNA) in ECs in a dose- and time-dependent
manner. G1/S-associated molecules that might account for
this block were not changed, because Hcy did not affect mRNA and
protein expression of cyclin D1 and cyclin E. Cyclin D1- and
E-associated kinase activities were unchanged. In contrast, cyclin
A-associated kinase activity and CDK2 kinase activity were markedly
suppressed. Nuclear run-on assay demonstrated that Hcy decreased the
transcription rate of the cyclin A gene but had no effect on the
half-life of cyclin A mRNA. In transient transfection experiments, Hcy
significantly inhibited cyclin A promoter activity in endothelial
cells, but not in vascular smooth muscle cells. Finally,
adenovirus-transduced cyclin A expression restored EC growth inhibition
and overcame the S phase block imposed by Hcy. Taken together, these
findings indicate that cyclin A is a critical functional target of
Hcy-mediated EC growth inhibition.
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