Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Li J.; Qi D.; Cheng H.Hu X.Miller E.J.Wu X.Russell K.S.Mikush N.Zhang J.Xiao L.Sherwin R.S.Young L.H.

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Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

机译：Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第40期|16133-16138|共6页
作者
Li J.; Qi D.; Cheng H.Hu X.Miller E.J.Wu X.Russell K.S.Mikush N.Zhang J.Xiao L.Sherwin R.S.Young L.H.;
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作者单位

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, United States;

Department of Medicine, Boston University, Boston, MA 02118, United States;

University of Florida Shands Cancer Center, Department of Anatomy and Cell Biology, College of Medicine, Gainesville, FL 32610, United StatesDepartment of Pharmacology and Toxicology, University at Buffalo, State University of New York, Buffalo, NY 14214, United StatesSection of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Cardiac function; Metabolism;

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

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