Regulation of Bcl-xL Expression in Lung Vascular Smooth Muscle

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.