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This Article Full Text Full Text (PDF) All Versions of this Article: 287/6/H2369    most recent 00422.2004v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Xi, L. Articles by Kukreja, R. C. Search for Related Content PubMed PubMed Citation Articles by Xi, L. Articles by Kukreja, R. C.

Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1 and AP-1 and iNOS signaling

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298-0281

Submitted 6 May 2004 ; accepted in final form 23 July 2004

Acute systemic hypoxia induces delayed cardioprotection against ischemia (I)-reperfusion (R) injury via inducible nitric oxide synthase (iNOS)-dependent mechanism. Because CoCl₂ is known to elicit hypoxia-like responses, we hypothesized that this chemical would mimic the delayed preconditioning effect in the heart. Adult male mice were pretreated with CoCl₂ or saline. The hearts were isolated 24 h later and subjected to 20 min of global I and 30 min of R in Langendorff mode. Myocardial infarct size (% of risk area; mean ± SE, n = 6–8/group) was reduced in mice pretreated with 30 mg/kg CoCl₂ (16.1 ± 3.1% vs. 27.6 ± 3.3% with saline control; P < 0.05) without compromising postischemic cardiac function. Higher doses of CoCl₂ failed to induce similar protection. Electrophoretic mobility gel shift assay demonstrated significant enhancement in DNA binding activity of hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) in nuclear extracts from CoCl₂-treated hearts. Activation of HIF-1 and AP-1 was evident at 30 min and sustained for the next 4 h after CoCl₂ injection. In contrast, CoCl₂-induced protection was independent of NF-B activation because no DNA binding or p65 translocation was observed in nuclear extracts. Also, CoCl₂-induced cardioprotection was preserved in p50 subunit NF-B-knockout (KO) mice (11.1 ± 3.0% vs. 25.1 ± 5.0% in saline-treated p50-KO mice; P < 0.05). The infarct-limiting effect of CoCl₂ was absent in iNOS-KO mice (20.9 ± 3.0%). We conclude that in vivo administration of CoCl₂ preconditions the heart against I/R injury. The delayed protective effect of CoCl₂ is achieved through a distinctive signaling mechanism involving HIF-1, AP-1, and iNOS but independent of NF-B activation.

ischemia-reperfusion injury; myocardial infarction; hypoxia; nitric oxide synthase; transcription factors

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