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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H1078    most recent 00937.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tian, F. Articles by Akyürek, L. M. PubMed PubMed Citation Articles by Tian, F. Articles by Akyürek, L. M.

Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis

Fei Tian,^1,* Xianghua Zhou,^1,2,* Johannes Wikström,³ Helen Karlsson,⁴ Helén Sjöland,⁵ Li-Ming Gan,⁵ Jan Borén,^1,5, and Levent M. Akyürek^1,2,

¹Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, and ²Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Göteborg, ³Bioscience, AstraZeneca Research and Development, Mölndal, ⁴Department of Molecular and Clinical Medicine, Linköping University, Linköping, ⁵Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Göteborg, Sweden

Submitted 27 August 2008 ; accepted in final form 2 July 2009

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/mm², P < 0.01), and arteriolar density (from 8.04 ± 0.76 to 10.34 ± 0.69 arterioles/mm², 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.

myocardial infarction; apoptosis; migration; adhesion