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Transforming growth factor-β1 protects against pulmonary artery endothelial cell apoptosis via ALK5

Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island

Submitted 27 September 2007 ; accepted in final form 28 April 2008

Transforming growth factor (TGF)-β1 has been reported to cause endothelial cell apoptosis. However, conflicting data have also demonstrated that TGF-β1 promotes endothelial cell survival. In this study, the effect of TGF-β1 on apoptosis of cultured bovine pulmonary artery endothelial cells (PAEC) induced by multiple stimuli was investigated. TGF-β1 protected against apoptosis of bovine PAEC induced by serum deprivation or the VEGF receptor inhibitor SU-5416, but not by UV light exposure or TNF. Neither caspase-8 nor caspase-12 was activated by serum deprivation or the VEGF receptor blocker. However, blockade of VEGF receptors activated caspase-9, an effect that was abolished by TGF-β1. Furthermore, serum deprivation and inhibition of VEGF receptors significantly decreased the protein level of Bcl-2, an effect that was also abrogated by TGF-β1. In addition, the baseline level of Bcl-2 was enhanced by TGF-β1 and reduced by inhibition of activin receptor-like kinase 5 (ALK5), a TGF-β1 type I receptor. Furthermore, inhibition of ALK5 caused apoptosis of bovine PAEC. These results suggest that TGF-β1 signaling is critical for maintenance of bovine PAEC survival. Finally, the protective effects of TGF-β1 on bovine PAEC apoptosis and Bcl-2 reduction were abolished by ALK5 inhibition, but not by inhibition of non-SMAD signaling pathways. Also, TGF-β1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition. The results of this study suggest that TGF-β1 protects against bovine PAEC apoptosis, possibly through ALK5-mediated Bcl-2 induction and subsequent inhibition of the mitochondria-mediated intrinsic pathway of apoptosis. Understanding the mechanism by which TGF-β1 promotes endothelial cell survival may provide a better treatment for apoptosis-dependent vascular diseases, such as emphysema.

Bcl-2; pulmonary artery hypertension; SMAD

This article has been cited by other articles:

				Q. Lu, B. Patel, E. O. Harrington, and S. Rounds Transforming growth factor-{beta}1 causes pulmonary microvascular endothelial cell apoptosis via ALK5 Am J Physiol Lung Cell Mol Physiol, May 1, 2009; 296(5): L825 - L838. [Abstract] [Full Text] [PDF]