(Circulation. 1997;95:1523-1531.)
© 1997 American Heart Association, Inc.
Articles |
Blocking the Endogenous Increase in HSP 72 Increases Susceptibility to Hypoxia and Reoxygenation in Isolated Adult Feline Cardiocytes
From Cardiology Research, the VA Medical Center and Baylor College of Medicine, Houston, Tex.
Correspondence to Anne A. Knowlton, MD, Cardiology Research, 151C, VA Medical Center, 2002 Holcombe, Houston, TX 77030.
Background Heat shock protein (HSP) 72 is a ubiquitous protein that is rapidly induced in response to stress and is thought to constitute an endogenous protective response. Previously, work has focused on the effect of overexpression of HSP 72 in various cell types. We were interested in testing the hypothesis that blocking the increase in HSP 72 that occurs in response to hypoxia or ischemia would be deleterious, thus showing that the endogenous response in cells, particularly cardiac cells, is an important line of defense against cell injury.
Methods and Results Isolated adult feline cardiocytes were treated with a 14-mer phosphorothioate antisense (AS) to HSP 72 and then exposed to mild (8 hours) or severe (12 hours) hypoxia. With mild hypoxia, an increase in LDH release, a decrease in MTT uptake, and a decrease in live-to-dead ratios were seen in AS-treated cells compared with control cells and cells treated with the complementary sense sequence or with AS to major histocompatibility complex I. AS treatment converted mild hypoxic injury to a pattern of cell injury seen with severe injury. After severe hypoxia, all treatment groups showed an increase in LDH, a decrease in MTT uptake, and a decrease in live-to-dead ratios; AS-treated cells had the greatest increase in cell injury. AS treatment produced a 40% decrease in HSP 72 levels after hypoxia compared with control cells treated with hypoxia. A dose-response study showed inhibition of the increase in HSP 72 with as little as 5 µg (1.24 µmol/L) of AS.
Conclusions (1) Blocking an increase in HSP 72 with AS increases the susceptibility of adult cardiac myocytes to hypoxic injury. (2) HSP 72 is an important part of the normal cell response to stress and is important in protecting cardiac myocytes from hypoxia and reoxygenation.
Key Words: proteins, heat shock • hypoxia • ischemia • antisense • major histocompatibility complex 1
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