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lüll Transforming growth factor-beta1 protects against pulmonary artery endothelial cell apoptosis via ALK5 Lu QAm J Physiol Lung Cell Mol Physiol 2008[Jul]; 295 (1): L123-33Transforming growth factor (TGF)-beta1 has been reported to cause endothelial cell apoptosis. However, conflicting data have also demonstrated that TGF-beta1 promotes endothelial cell survival. In this study, the effect of TGF-beta1 on apoptosis of cultured bovine pulmonary artery endothelial cells (PAEC) induced by multiple stimuli was investigated. TGF-beta1 protected against apoptosis of bovine PAEC induced by serum deprivation or the VEGF receptor inhibitor SU-5416, but not by UV light exposure or TNFalpha. 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-beta1. Furthermore, serum deprivation and inhibition of VEGF receptors significantly decreased the protein level of Bcl-2, an effect that was also abrogated by TGF-beta1. In addition, the baseline level of Bcl-2 was enhanced by TGF-beta1 and reduced by inhibition of activin receptor-like kinase 5 (ALK5), a TGF-beta1 type I receptor. Furthermore, inhibition of ALK5 caused apoptosis of bovine PAEC. These results suggest that TGF-beta1 signaling is critical for maintenance of bovine PAEC survival. Finally, the protective effects of TGF-beta1 on bovine PAEC apoptosis and Bcl-2 reduction were abolished by ALK5 inhibition, but not by inhibition of non-SMAD signaling pathways. Also, TGF-beta1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition. The results of this study suggest that TGF-beta1 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-beta1 promotes endothelial cell survival may provide a better treatment for apoptosis-dependent vascular diseases, such as emphysema.|Animals[MESH]|Apoptosis/drug effects/*physiology/radiation effects[MESH]|Caspase 12/metabolism[MESH]|Caspase 8/metabolism[MESH]|Cattle[MESH]|Cell Survival/drug effects/radiation effects[MESH]|Emphysema/metabolism[MESH]|Endothelial Cells/*metabolism[MESH]|Enzyme Activation[MESH]|Humans[MESH]|Indoles/pharmacology[MESH]|Mitochondria/metabolism[MESH]|Protein Kinase Inhibitors/pharmacology[MESH]|Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism[MESH]|Proto-Oncogene Proteins c-bcl-2/metabolism[MESH]|Pulmonary Artery/*metabolism[MESH]|Pyrroles/pharmacology[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/antagonists & inhibitors/*metabolism[MESH]|Receptors, Vascular Endothelial Growth Factor/biosynthesis[MESH]|Signal Transduction/drug effects/*physiology/radiation effects[MESH]|Smad Proteins/metabolism[MESH]|Transforming Growth Factor beta1/*metabolism[MESH]|Tumor Necrosis Factor-alpha/metabolism[MESH]|Ultraviolet Rays[MESH] |