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

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-f...