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Am J Physiol Heart Circ Physiol (July 29, 2004). doi:10.1152/ajpheart.00422.2004
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Submitted on May 6, 2004
Accepted on July 23, 2004

Cobalt Chloride Induces Delayed Cardiac Preconditioning in Mice Through Selective Activation of HIF-1{alpha} / AP-1 and iNOS Signaling

Lei Xi1, Mohiuddin Taher1, Chang Yin1, Fadi Salloum1, and Rakesh C Kukreja1*

1 Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Va, USA

* To whom correspondence should be addressed. E-mail: rakesh{at}hsc.vcu.edu.

Acute systemic hypoxia induces delayed cardioprotection against ischemia (I)-reperfusion (R) injury via inducible nitric oxide synthase (iNOS)-dependent mechanism. Since cobalt chloride (CoCl2) is known to elicit hypoxia-like responses, we hypothesized that this chemical would mimic delayed preconditioning effect in the heart. Adult male mice were pretreated with CoCl2 or saline. The hearts were isolated 24 hours later and subjected to 20 min of global I and 30 min of R in Langendorff mode. Myocardial infarct size (% of risk area; mean±SEM, n=6-8/group) was reduced in mice pretreated with 30 mg/kg CoCl2 (16.1±3.1%, versus saline control 27.6±3.3%, P<0.05) without compromising post-ischemic 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{alpha} (HIF-1{alpha}) and activator protein 1 (AP-1) in nuclear extracts from CoCl2-treated hearts. Activation of HIF-1{alpha} and AP-1 was evident at 30 min and sustained for the next 4 hours after CoCl2 injection. In contrast, CoCl2-induced protection was independent of nuclear factor kappa B (NF-{kappa}B) activation because no DNA binding or p65 translocation was observed in nuclear extracts. Also, CoCl2-induced cardioprotection was preserved in p50 subunit NF-{kappa}B knockout mice (11.1±3.0%, P<0.05 versus saline-treated p50 knockout mice 25.1±5.0%). The infarct-limiting effect of CoCl2 was absent in iNOS knockout 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{alpha}, AP-1, iNOS, but independent of NF-{kappa}B activation.




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