title: Physiological cyclic strain promotes endothelial cell survival via the induction of heme oxygenase-1.
abstract: Endothelial cells (ECs) are constantly subjected to cyclic strain that arises from periodic change in vessel wall diameter as a result of pulsatile blood flow. Application of physiological levels of cyclic strain inhibits EC apoptosis; however, the underlying mechanism is not known. Since heme oxygenase-1 (HO-1) is a potent inhibitor of apoptosis, the present study investigated whether HO-1 contributes to the antiapoptotic action of cyclic strain. Administration of physiological cyclic strain (6% at 1 Hz) to human aortic ECs stimulated an increase in HO-1 activity, protein, and mRNA expression. The induction of HO-1 was preceded by a rise in reactive oxygen species (ROS) and Nrf2 protein expression. Cyclic strain also stimulated an increase in HO-1 promoter activity that was prevented by mutating the antioxidant responsive element in the promoter or by overexpressing dominant-negative Nrf2. In addition, the strain-mediated induction of HO-1 and activation of Nrf2 was abolished by the antioxidant N-acetyl-l-cysteine. Finally, application of cyclic strain blocked inflammatory cytokine-mediated EC death and apoptosis. However, the protective action of cyclic strain was reversed by the HO inhibitor tin protoporphyrin-IX and was absent in ECs isolated from HO-1-deficient mice. In conclusion, the present study demonstrates that a hemodynamically relevant level of cyclic strain stimulates HO-1 gene expression in ECs via the ROS-Nrf2 signaling pathway to inhibit EC death. The ability of cyclic strain to induce HO-1 expression may provide an important mechanism by which hemodynamic forces promote EC survival and vascular homeostasis.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Liu
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: William
authors.initials: W
authors.lastname: Durante
mesh_terms: D006801:Humans; D000111:Acetylcysteine / Q000494:pharmacology; D061745:Antioxidant Response Elements; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D002470:Cell Survival; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D008665:Metalloporphyrins / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D013312:Stress, Physiological; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000818:Animals; D051379:Mice
chemical_list: D000111:Acetylcysteine; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D051547:Heme Oxygenase-1; D008665:Metalloporphyrins; D051267:NF-E2-Related Factor 2; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D012333:RNA, Messenger; C032628:tin protoporphyrin IX
keywords: endothelium; hemodynamic forces; vascular biology