Document Detail

Transforming growth factor-beta1 causes pulmonary microvascular endothelial cell apoptosis via ALK5.
MedLine Citation:
PMID:  19270180     Owner:  NLM     Status:  MEDLINE    
We have previously shown that transforming growth factor (TGF)-beta1 protected against main pulmonary artery endothelial cell (PAEC) apoptosis induced by serum deprivation and VEGF receptor blockade through a mechanism associated with ALK5-mediated Bcl-2 upregulation. In the current study, we investigated the effect of TGF-beta1 on pulmonary microvascular endothelial cell (PMVEC) apoptosis. We found that, in contrast to the results seen in conduit PAEC, TGF-beta1 caused apoptosis of PMVEC, an effect that was also dependent on ALK5 activity. We noted that non-SMAD signaling pathways did not play a role in TGF-beta1-induced apoptosis. Both SMAD2 and SMAD1/5 were activated upon exposure to TGF-beta1. TGF-beta1-induced activation of SMAD2, but not SMAD1/5, was abolished by ALK5 inhibition, an effect that associated with prevention of TGF-beta1-induced apoptosis. These results suggest that SMAD2 is important in TGF-beta1-induced apoptosis of PMVEC. While caspase-12 activity was not altered, caspase-8 was activated by TGF-beta1, an effect that correlated with a reduction of cFLIP protein levels. Additionally, TGF-beta1 decreased Bcl-2 protein levels and induced cytochrome c cytosolic redistribution. These results suggest that TGF-beta1 caused apoptosis of PMVEC likely through both caspase-8-dependent extrinsic pathway and mitochondria-mediated intrinsic pathway. We noted that inhibition of ALK5 attenuated serum deprivation-induced apoptosis, an effect that correlated with increased expression and activation of CREB and its potential target genes, Bcl-2 and cFLIP. These results suggest that CREB may be important in mediating apoptosis resistance of PMVEC upon ALK5 inhibition perhaps through upregulation of Bcl-2 and cFLIP. Finally, we noted that SMAD1/5 were activated upon ALK5 inhibition in the presence of low levels of TGF-beta1, an effect associated with enhanced endothelial proliferation. We speculate that imbalance of ALK1 and ALK5 may contribute to the development of pulmonary artery hypertension.
Qing Lu; Bhuvic Patel; Elizabeth O Harrington; Sharon Rounds
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-03-06
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  296     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-29     Completed Date:  2009-06-17     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L825-38     Citation Subset:  IM    
Providence VA Medical Center, Research Services, Providence, RI 02908, USA.
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MeSH Terms
Activin Receptors / antagonists & inhibitors,  metabolism*
Apoptosis / drug effects*
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Caspase 8 / metabolism
Cell Survival / drug effects
Cyclic AMP Response Element-Binding Protein / metabolism
Endothelial Cells / cytology*,  drug effects,  enzymology
Enzyme Activation / drug effects
Lung / blood supply*,  cytology*
Microvessels / cytology*
Mitochondrial Membranes / drug effects,  metabolism
Permeability / drug effects
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-bcl-2 / metabolism
Receptors, Transforming Growth Factor beta
Signal Transduction / drug effects
Smad Proteins / metabolism
Transforming Growth Factor beta1 / pharmacology*
Grant Support
Reg. No./Substance:
0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/Cyclic AMP Response Element-Binding Protein; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Transforming Growth Factor beta; 0/Smad Proteins; 0/Transforming Growth Factor beta1; EC type I receptor; EC Kinases; EC Receptors; EC 3.4.22.-/Caspase 8

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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