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

• DOI: 10.1152/ajpheart.00422.2004
• Publication Date: 2004-07-30T00:15:05Z
• Authors: Lei Xi; Mohiuddin Taher; Chang Yin; Fadi Salloum; Rakesh C. Kukreja
• Keywords: Cobalt chloride

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