Published ahead of print on February 1, 2007, doi:10.1165/rcmb.2006-0359OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 6, June 2007, 678-687 A more recent version of this article appeared on June 1, 2007
Submitted on September 23, 2006 Regulation of Bcl-xL Expression in Lung Vascular Smooth MuscleYuichiro J Suzuki1*,1 Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA, 2 Department of Medicine, Division of Pulmonary and Critical Care Medicine, George Washington University Medical Center, Washington, DC, USA, 3 Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA * To whom correspondence should be addressed. E-mail: ys82{at}georgetown.edu.
Pulmonary hypertension is characterized by thickened pulmonary arterial walls due to increased number of pulmonary artery smooth muscle cells (PASMC). Apoptosis of PASMC may play important roles in regulating the PASMC number and may be useful for reducing pulmonary vascular thickening. The present study examined the regulation of an anti-apoptotic protein Bcl-xL. Bcl-xL expression was found to be increased in the pulmonary artery of chronic hypoxia treated rats with pulmonary vascular remodeling. Adenovirus-mediated gene transfer of Bcl-xL indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced Bcl-xL expression by targeting the bcl-xL promoter. The bcl-xL promoter contains two GATA elements, and SNP decreases the GATA-4 DNA binding activity. Overexpression of GATA-4 attenuated the SNP-mediated suppression of Bcl-xL expression, providing direct evidence for the role of GATA-4 in Bcl-xL gene transcription. We identified that SNP targets the 250 proximal region of the gata4 promoter and suppresses its gene transcription. Thus, inducers of pulmonary hypertension enhance anti-apoptotic Bcl-xL gene transcription, which can be suppressed by targeting the gata4 gene transcription.
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