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Regulation of Bcl-x_L Expression in Lung Vascular Smooth Muscle

Department of Pharmacology, Georgetown University Medical Center, and Division of Pulmonary and Critical Care Medicine, Department of Medicine, George Washington University Medical Center, Washington, DC; and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Dr. Yuichiro J. Suzuki, Department of Pharmacology, Georgetown University Medical Center, NW403 Medical-Dental Building, 3900 Reservoir Road NW, Washington, DC 20057. 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 an important role 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-x_L. Bcl-x_L 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-x_L indeed showed that this protein has anti-apoptotic activities in PASMC. Treatment of remodeled pulmonary artery with sodium nitroprusside (SNP) reduced Bcl-x_L expression by targeting the bcl-x_L promoter. The bcl-x_L 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-x_L expression, providing direct evidence for the role of GATA-4 in Bcl-x_L gene transcription. We established 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-x_L gene transcription, which can be suppressed by targeting gata4 gene transcription.

Key Words: apoptosis • genes • pulmonary hypertension • smooth muscle

CLINICAL RELEVANCE Recently, apoptosis-based therapeutic strategies to reduce pulmonary vascular thickening have gained attention. Understanding apoptotic regulation in pulmonary vascular smooth muscle should promote such strategies to treat pulmonary hypertension.