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.

[1]  A. Tanswell,et al.  Endothelin-1 Inhibits Apoptosis of Pulmonary Arterial Smooth Muscle in the Neonatal Rat , 2006, Pediatric Research.

[2]  A. Harmar,et al.  Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease , 2005, Circulation research.

[3]  P. Jones,et al.  Epidermal Growth Factor Receptor Blockade Mediates Smooth Muscle Cell Apoptosis and Improves Survival in Rats With Pulmonary Hypertension , 2005, Circulation.

[4]  S. Archer,et al.  Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. , 2005, The Journal of clinical investigation.

[5]  B. Ma,et al.  Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury. , 2005, The Journal of clinical investigation.

[6]  J. Dyck,et al.  Dichloroacetate Prevents and Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis , 2004, Circulation research.

[7]  J. Yuan,et al.  Overexpression of human KCNA5 increases IK V and enhances apoptosis. , 2004, American journal of physiology. Cell physiology.

[8]  R. Schwartz,et al.  Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Sorenson.  Bcl-2 family members and disease. , 2004, Biochimica et biophysica acta.

[10]  S. Wedgwood,et al.  Molecular mechanisms of nitric oxide-induced growth arrest and apoptosis in fetal pulmonary arterial smooth muscle cells. , 2003, Nitric oxide : biology and chemistry.

[11]  G. Berry,et al.  Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells , 2003, Circulation.

[12]  J. Molkentin,et al.  Activation of GATA-4 by Serotonin in Pulmonary Artery Smooth Muscle Cells* , 2003, The Journal of Biological Chemistry.

[13]  Yuichiro J Suzuki,et al.  Hepatocyte Growth Factor Induces GATA-4 Phosphorylation and Cell Survival in Cardiac Muscle Cells* , 2003, The Journal of Biological Chemistry.

[14]  Yuichiro J Suzuki,et al.  Anthracycline-induced suppression of GATA-4 transcription factor: implication in the regulation of cardiac myocyte apoptosis. , 2003, Molecular pharmacology.

[15]  HironoriNakagami,et al.  Role of Angiotensin II–Regulated Apoptosis Through Distinct AT1 and AT2 Receptors in Neointimal Formation , 2002 .

[16]  M. Yacoub,et al.  ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. , 2002, American journal of respiratory and critical care medicine.

[17]  M. Yacoub,et al.  ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. , 2002, American journal of respiratory and critical care medicine.

[18]  J. Yuan,et al.  Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells. , 2002, American journal of physiology. Heart and circulatory physiology.

[19]  M. Humbert,et al.  Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. , 2001, The Journal of clinical investigation.

[20]  R. Day,et al.  Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis. , 2001, Free radical biology & medicine.

[21]  M. Beato,et al.  Promoter Choice Influences Alternative Splicing and Determines the Balance of Isoforms Expressed from the Mousebcl-X Gene* , 2001, The Journal of Biological Chemistry.

[22]  N. Voelkel,et al.  Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension: A Gene Microarray Analysis , 2001, Circulation research.

[23]  G. Juliá-Serdá,et al.  One-year continuous inhaled nitric oxide for primary pulmonary hypertension. , 2001, Chest.

[24]  D A Lynch,et al.  Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. , 2001, American journal of respiratory and critical care medicine.

[25]  M. Wicha,et al.  A bcl-xS adenovirus selectively induces apoptosis in transformed cells compared to normal mammary cells. , 2000, Neoplasia.

[26]  J. Herget,et al.  Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. , 2000, Physiological reviews.

[27]  Y. Kaneda,et al.  Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts. , 1999, Cardiovascular research.

[28]  G. Poiani,et al.  Role of proteolysis and apoptosis in regression of pulmonary vascular remodeling. , 2000, Physiological research.

[29]  Adriana,et al.  Molecular Mechanisms , 1999 .

[30]  S. Orkin,et al.  GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. , 1999, Blood.

[31]  P. Jones,et al.  Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. , 1999, Circulation research.

[32]  D. Nakayama,et al.  Nitric oxide causes apoptosis in pulmonary vascular smooth muscle cells. , 1998, The Journal of surgical research.

[33]  Jennifer L Hall,et al.  Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease , 1998, Nature Medicine.

[34]  M. Seldin,et al.  Genomic organization, promoter region analysis, and chromosome localization of the mouse bcl-x gene. , 1997, Journal of immunology.

[35]  C. Bloch,et al.  Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. , 1996, Cancer research.

[36]  M. Horiuchi,et al.  Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. , 1996, Circulation research.

[37]  W. Auger,et al.  Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. , 1996, Chest.

[38]  M. Clarke,et al.  bcl-xs gene therapy induces apoptosis of human mammary tumors in nude mice. , 1996, Cancer research.

[39]  C. Thompson,et al.  Bcl-x Antagonizes the Protective Effects of Bcl-x(*) , 1996, The Journal of Biological Chemistry.

[40]  C. Thompson,et al.  Bcl-x(S) anatagonizes the protective effects of Bcl-x(L). , 1996, The Journal of biological chemistry.

[41]  J. Dick,et al.  A recombinant bcl-x s adenovirus selectively induces apoptosis in cancer cells but not in normal bone marrow cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Clarke,et al.  Overexpression of Bcl-XS sensitizes MCF-7 cells to chemotherapy-induced apoptosis. , 1995, Cancer research.

[43]  G. Snell,et al.  Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. , 1995, American journal of respiratory and critical care medicine.

[44]  C. Thompson,et al.  bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death , 1993, Cell.

[45]  Jesse D. Roberts,et al.  Inhaled nitric oxide in persistent pulmonary hypertension of the newborn , 1992, The Lancet.

[46]  B. Fanburg,et al.  Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. , 1991, Circulation research.