title: Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis.
abstract: Previous studies have shown that exposure to chronic hypoxia protects against myocardial infarction, but little is known about the cellular and molecular mechanisms involved. Here we observed that chronic hypoxia for 3 wk resulted in improved survival of mice (from 64% to 83%), reduced infarction size (from 45 +/- 4% to 32 +/- 4%, P < 0.05), increased cardiac ejection fraction (from 19 +/- 4% to 35 +/- 5%, P < 0.05), coronary flow velocity under adenosine-induced hyperemia (from 58 +/- 2 to 75 +/- 5 cm/s, P < 0.05), myocardial capillary density (from 3,772 +/- 162 to 4,760 +/- 197 capillaries/mm(2), P < 0.01), and arteriolar density (from 8.04 +/- 0.76 to 10.34 +/- 0.69 arterioles/mm(2), P < 0.05) 3 wk after myocardial infarction. With two-dimensional gel electrophoresis, we identified that protein disulfide isomerase (PDI) was highly upregulated in hypoxic myocardial capillary endothelial cells. The loss of PDI function in endothelial cells by small interfering RNA significantly increased the number of apoptotic cells (by 3.4-fold at hypoxia, P < 0.01) and reduced migration (by 52% at hypoxia, P < 0.001) and adhesion to collagen I (by 42% at hypoxia, P < 0.01). In addition, the specific inhibition of PDI by PDI small interfering RNA (by 46%, P < 0.01) and bacitracin (by 72%, P < 0.001) reduced the formation of tubular structures by endothelial cells. Our data indicate that chronic hypoxic exposure improves coronary blood flow and protects the myocardium against infarction. These beneficial effects may be partly explained by the increased endothelial expression of PDI, which protects cells against apoptosis and increases cellular migration, adhesion, and tubular formation. The increased PDI expression in endothelial cells may be a novel mechanism to protect the myocardium against myocardial ischemic diseases.
authors.affiliation: Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, University of Gothenburg, SE-413 45 Göteborg, Sweden.
authors.forename: Fei
authors.initials: F
authors.lastname: Tian
authors.forename: Xianghua
authors.initials: X
authors.lastname: Zhou
authors.forename: Johannes
authors.initials: J
authors.lastname: Wikström
authors.forename: Helen
authors.initials: H
authors.lastname: Karlsson
authors.forename: Helén
authors.initials: H
authors.lastname: Sjöland
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Gan
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001160:Arterioles / Q000502:physiology; D001835:Body Weight; D002196:Capillaries / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D003326:Coronary Circulation / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009929:Organ Size; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006454:Hemoglobins; D034741:RNA, Small Interfering; D019704:Protein Disulfide-Isomerases