title: Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart.
abstract: Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) on cardiomyocytes and confers protection against ischemia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis mitigates against ischemia/reperfusion injury remain incompletely delineated. Activation of AMP-activated protein kinase (AMPK) also limits cardiac damage during ischemia/reperfusion. AMPK is classically activated by alterations in cellular energetics; however, hormones, cytokines, and additional autocrine/paracrine factors also modulate its activity. We examined the effects of both the endogenous cardiac Ucn2 autocrine/paracrine pathway and Ucn2 treatment on AMPK regulation. Ucn2 treatment increased AMPK activation and downstream acetyl-CoA carboxylase phosphorylation and glucose uptake in isolated heart muscles. These actions were blocked by the CRFR2 antagonist anti-sauvagine-30 and by a PKCε translocation-inhibitor peptide (εV1-2). Hypoxia-induced AMPK activation was also blunted in heart muscles by preincubation with either anti-sauvagine-30, a neutralizing anti-Ucn2 antibody, or εV1-2. Treatment with Ucn2 in vivo augmented ischemic AMPK activation and reduced myocardial injury and cardiac contractile dysfunction after regional ischemia/reperfusion in mice. Ucn2 also directly activated AMPK in ex vivo-perfused mouse hearts and diminished injury and contractile dysfunction during ischemia/reperfusion. Thus, both Ucn2 treatment and the endogenous cardiac Ucn2 autocrine/paracrine pathway activate AMPK signaling pathway, via a PKCε-dependent mechanism, defining a Ucn2-CRFR2-PKCε-AMPK pathway that mitigates against ischemia/reperfusion injury.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Dake
authors.initials: D
authors.lastname: Qi
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Hu
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Nicole
authors.initials: N
authors.lastname: Mikush
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D009206:Myocardium / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D054832:Urocortins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D057134:Antibodies, Neutralizing; C101531:CRF receptor type 2; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C116607:antisauvagine 30; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
keywords: cardiac function; metabolism
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