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- Title
Urocortin Stimulates Glucose Uptake in the Hypoxic Heart by Activation of PKCε-AMPK Pathway.
- Authors
Ji Li; Haiying Cheng; Hu, Jennifer; Cheng Liao; Miller, Edward J.; Xiaohong Wu; Sherwin, Robert S.; Young, Lawrence H.
- Abstract
Urocortin (Ucn), is a peptide in the corticotrophin-releasing factor (CRF) family, that was originally identified in the rat brain, but is also expressed in other tissues including the heart. Ucn binds with high affinity to the CRF receptor 2 subtype (CRFR2), which like Ucn is expressed in cardiac myocytes. The Ucn-CRFR2 pathway regulates energy homeostasis in the central nervous system, and also protects the heart from injury during ischemia/reperfusion, in part by activating ε isoform of protein kinase C (PKCε). However, the metabolic effects of Ucn in the heart and the mechanism through which it protects against ischemic injury are unknown. AMP-activated protein kinase (AMPK) is activated during cardiac ischemia by changes in cellular energetics, but is also modulated by additional mechanisms. AMPK has a key role in mediating ischemic glucose uptake and in protecting the heart against ischemic injury. The purpose of this study was to evaluate whether 1) Ucn stimulates the AMPK pathway and 2) PKCε 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 Thr[sup 172] phosphorylation (2.1-fold, p<0.05 vs. control) and increased glucose uptake (1.9-fold, p<0.01 vs. control). The CRFR2 antagonist anti-sauvagine-30 (a-Svg-30, 100 nM), neutralizing anti-Ucn antibody and a PKCε translocation-inhibitor peptide, eliminated Ucn-stimulated AMPK Thr[sup 172] phosphorylation, downstream acetyl CoA carboxylase (ACC) Ser[sup 79] phosphorylation and glucose uptake (p<0.01 vs. Ucn alone). Moreover, the AMPK inhibitor, compound C (10µM), blocked Ucn-stimulated glucose uptake by 82% (p<0.01 vs. Ucn alone). Hypoxia (30 min) treatment stimulated heart muscle Ucn release, AMPK activation and glucose uptake (p<0.01 vs. control). The CRFR2 antagonist a-Svg-30, neutralizing anti-Ucn antibody and a PKCε translocation-inhibitor peptide partially blocked hypoxia-induced heart muscle AMPK activation (by 21%, 26% and 24%, respectively), ACC phosphorylation (by 19%, 22% and 20%) and glucose uptake (by 27%, 29% and 23%). Thus, Ucn in heart muscle contributes to glucose uptake during hypoxic stress by activating the PKCε-AMPK signaling pathway. These findings define novel mechanisms of Ucn action and AMPK activation that may have importance in the ischemic heart. ADA-Funded Research
- Subjects
PEPTIDES; GLUCOSE; HEART cells; MYOCARDIUM; HOMEOSTASIS; PROTEIN kinase C; PHOSPHORYLATION; HYPOXEMIA
- Publication
Diabetes, 2007, Vol 56, pA512
- ISSN
0012-1797
- Publication type
Article