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Heat Shock Protein 70 Prevents Hyperoxia-Induced Disruption of Lung Endothelial Barrier via Caspase-Dependent and AIF-Dependent Pathways.

Kondrikov D, Fulton D, Dong Z, Su Y - PLoS ONE (2015)

Bottom Line: Furthermore, we found that Hsp70 interacted with AIF in the cytosol in hyperoxic PAECs.Finally, the ROS scavenger NAC prevented the hyperoxia-induced increase in Hsp70 expression and reduced the interaction of Hsp70 with AIF in hyperoxic PAECs.Association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States of America.

ABSTRACT
Exposure of pulmonary artery endothelial cells (PAECs) to hyperoxia results in a compromise in endothelial monolayer integrity, an increase in caspase-3 activity, and nuclear translocation of apoptosis-inducing factor (AIF), a marker of caspase-independent apoptosis. In an endeavor to identify proteins involved in hyperoxic endothelial injury, we found that the protein expression of heat-shock protein 70 (Hsp70) was increased in hyperoxic PAECs. The hyperoxia-induced Hsp70 protein expression is from hspA1B gene. Neither inhibition nor overexpression of Hsp70 affected the first phase barrier disruption of endothelial monolayer. Nevertheless, inhibition of Hsp70 by using the Hsp70 inhibitor KNK437 or knock down Hsp70 using siRNA exaggerated and overexpression of Hsp70 prevented the second phase disruption of lung endothelial integrity. Moreover, inhibition of Hsp70 exacerbated and overexpression of Hsp70 prevented hyperoxia-induced apoptosis, caspase-3 activation, and increase in nuclear AIF protein level in PAECs. Furthermore, we found that Hsp70 interacted with AIF in the cytosol in hyperoxic PAECs. Inhibition of Hsp70/AIF association by KNK437 correlated with increased nuclear AIF level and apoptosis in KNK437-treated PAECs. Finally, the ROS scavenger NAC prevented the hyperoxia-induced increase in Hsp70 expression and reduced the interaction of Hsp70 with AIF in hyperoxic PAECs. Together, these data indicate that increased expression of Hsp70 plays a protective role against hyperoxia-induced lung endothelial barrier disruption through caspase-dependent and AIF-dependent apoptotic pathways. Association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis. The hyperoxia-induced increase in Hsp70 expression and Hsp70/AIF interaction is contributed to ROS formation.

No MeSH data available.


Related in: MedlinePlus

A schematic pathway illustrating the role of Hsp70 in hyperoxic lung endothelial barrier disruption.Hyperoxia induces an increase in Hsp70 expression which plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via caspase- and AIF-dependent mechanism in hyperoxic lung endothelial injury.
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pone.0129343.g010: A schematic pathway illustrating the role of Hsp70 in hyperoxic lung endothelial barrier disruption.Hyperoxia induces an increase in Hsp70 expression which plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via caspase- and AIF-dependent mechanism in hyperoxic lung endothelial injury.

Mentions: In summary, hyperoxia induces an increase in Hsp70 expression that is from hspA1B gene. We have demonstrated that Hsp70 plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via both caspase- and AIF-dependent mechanisms in oxygen toxicity (Fig 10). In addition, association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis. Manipulation of Hsp70 might be a novel therapy for acute lung injury in oxygen toxicity.


Heat Shock Protein 70 Prevents Hyperoxia-Induced Disruption of Lung Endothelial Barrier via Caspase-Dependent and AIF-Dependent Pathways.

Kondrikov D, Fulton D, Dong Z, Su Y - PLoS ONE (2015)

A schematic pathway illustrating the role of Hsp70 in hyperoxic lung endothelial barrier disruption.Hyperoxia induces an increase in Hsp70 expression which plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via caspase- and AIF-dependent mechanism in hyperoxic lung endothelial injury.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465980&req=5

pone.0129343.g010: A schematic pathway illustrating the role of Hsp70 in hyperoxic lung endothelial barrier disruption.Hyperoxia induces an increase in Hsp70 expression which plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via caspase- and AIF-dependent mechanism in hyperoxic lung endothelial injury.
Mentions: In summary, hyperoxia induces an increase in Hsp70 expression that is from hspA1B gene. We have demonstrated that Hsp70 plays a protective role against endothelial barrier disruption and lung endothelial apoptosis via both caspase- and AIF-dependent mechanisms in oxygen toxicity (Fig 10). In addition, association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis. Manipulation of Hsp70 might be a novel therapy for acute lung injury in oxygen toxicity.

Bottom Line: Furthermore, we found that Hsp70 interacted with AIF in the cytosol in hyperoxic PAECs.Finally, the ROS scavenger NAC prevented the hyperoxia-induced increase in Hsp70 expression and reduced the interaction of Hsp70 with AIF in hyperoxic PAECs.Association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States of America.

ABSTRACT
Exposure of pulmonary artery endothelial cells (PAECs) to hyperoxia results in a compromise in endothelial monolayer integrity, an increase in caspase-3 activity, and nuclear translocation of apoptosis-inducing factor (AIF), a marker of caspase-independent apoptosis. In an endeavor to identify proteins involved in hyperoxic endothelial injury, we found that the protein expression of heat-shock protein 70 (Hsp70) was increased in hyperoxic PAECs. The hyperoxia-induced Hsp70 protein expression is from hspA1B gene. Neither inhibition nor overexpression of Hsp70 affected the first phase barrier disruption of endothelial monolayer. Nevertheless, inhibition of Hsp70 by using the Hsp70 inhibitor KNK437 or knock down Hsp70 using siRNA exaggerated and overexpression of Hsp70 prevented the second phase disruption of lung endothelial integrity. Moreover, inhibition of Hsp70 exacerbated and overexpression of Hsp70 prevented hyperoxia-induced apoptosis, caspase-3 activation, and increase in nuclear AIF protein level in PAECs. Furthermore, we found that Hsp70 interacted with AIF in the cytosol in hyperoxic PAECs. Inhibition of Hsp70/AIF association by KNK437 correlated with increased nuclear AIF level and apoptosis in KNK437-treated PAECs. Finally, the ROS scavenger NAC prevented the hyperoxia-induced increase in Hsp70 expression and reduced the interaction of Hsp70 with AIF in hyperoxic PAECs. Together, these data indicate that increased expression of Hsp70 plays a protective role against hyperoxia-induced lung endothelial barrier disruption through caspase-dependent and AIF-dependent apoptotic pathways. Association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis. The hyperoxia-induced increase in Hsp70 expression and Hsp70/AIF interaction is contributed to ROS formation.

No MeSH data available.


Related in: MedlinePlus