Abstract 780: Cardiac Urocortin Stimulates Hypoxic Glucose Uptake through Activation of AMP-activated Protein Kinase
Urocortin (Ucn), originally identified in the brain, is a 40 amino acid peptide member of the corticotrophin-releasing factor (CRF) family and is also expressed in cardiac myocytes. Ucn binds with high affinity to the CRF receptor 2 subtype (CRFR2), which is expressed in cardiac myocytes. Ucn-CRFR2 pathway regulates energy homeostasis in the central nervous system and may also be important in the heart protecting from ischemia/reperfusion injury. While Ucn activates the extracellular signal-regulated kinase (ERK) pathway, the metabolic effects of Ucn in the heart and their contribution to Ucn-mediated protection are unknown. AMP-activated protein kinase (AMPK) is activated during cardiac ischemia by changes in cellular energetics, but also may be modulated by additional mechanisms and has a key role in mediating ischemic glucose uptake. The purpose of this study was to evaluate whether Ucn activates the AMPK pathway and contributes to hypoxia-stimulated cardiac AMPK activation and glucose uptake. In isolated rat heart left ventricular papillary muscles, under normoxic conditions, Ucn (100 nM) stimulated cardiac AMPK Thr172 phosphorylation (2.1-fold, p<0.05 vs. control) and increased cardiac muscle glucose uptake (1.9-fold, p<0.01 vs. control). Both the CRFR2 antagonist anti-sauvagine-30 (a-Svg-30, 100 nM), and neutralizing anti-Ucn antibody, eliminated Ucn-stimulated AMPK Thr172 phosphorylation, downstream acetyl CoA carboxylase (ACC) Ser79 phosphorylation and glucose uptake (p<0.01 vs. Ucn alone). The AMPK inhibitor, compound C (10 μM), blocked Ucn-stimulated glucose uptake by 82% (p<0.01 vs. Ucn alone). Hypoxia (30 min) treatment stimulated papillary muscle cardiac myocytes Ucn release, AMPK activation and glucose uptake (p<0.01 vs. control). Both the CRFR2 antagonist a-Svg-30 and neutralizing anti-Ucn antibody partially inhibited hypoxia-induced cardiac muscle AMPK activation (by 21% and 26%), ACC phosphorylation (by 19% and 22%) and glucose uptake (by 27% and 29%). Thus, Ucn is a cardiac peptide that contributes to glucose uptake during hypoxic stress by activating the AMPK signaling pathway. These results define novel mechanisms of both Ucn action and AMPK activation, that may have an important role in the ischemic heart.