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SHR Neuro Cancer Cardio Lipid Metab Microb

Walther, S; Pluteanu, F; Renz, S; Nikonova, Y; Maxwell, JT; Yang, LZ; Schmidt, K; Edwards, JN; Wakula, P; Groschner, K; Maier, LS; Spiess, J; Blatter, LA; Pieske, B; Kockskämper, J.
Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177.
Am J Physiol Heart Circ Physiol. 2014; 307(5):H689-H700 Doi: 10.1152/ajpheart.00694.2013 [OPEN ACCESS]
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Leading authors Med Uni Graz: Walther Stefanie
Co-authors Med Uni Graz: Groschner Klaus; Pieske Burkert Mathias; Wakula-Heinzel Paulina
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Abstract:: Urocortin 2 (Ucn2) is a cardioactive peptide exhibiting beneficial effects in normal and failing heart. In cardiomyocytes, it elicits cAMP- and Ca(2+)-dependent positive inotropic and lusitropic effects. We tested the hypothesis that, in addition, Ucn2 activates cardiac nitric oxide (NO) signaling and elucidated the underlying signaling pathways and mechanisms. In isolated rabbit ventricular myocytes, Ucn2 caused concentration- and time-dependent increases in phosphorylation of Akt (Ser473, Thr308), endothelial NO synthase (eNOS) (Ser1177), and ERK1/2 (Thr202/Tyr204). ERK1/2 phosphorylation, but not Akt and eNOS phosphorylation, was suppressed by inhibition of MEK1/2. Increased Akt phosphorylation resulted in increased Akt kinase activity and was mediated by corticotropin-releasing factor 2 (CRF2) receptors (astressin-2B sensitive). Inhibition of phosphatidylinositol 3-kinase (PI3K) diminished both Akt as well as eNOS phosphorylation mediated by Ucn2. Inhibition of protein kinase A (PKA) reduced Ucn2-induced phosphorylation of eNOS but did not affect the increase in phosphorylation of Akt. Conversely, direct receptor-independent elevation of cAMP via forskolin increased phosphorylation of eNOS but not of Akt. Ucn2 increased intracellular NO concentration ([NO]i), [cGMP], [cAMP], and cell shortening. Inhibition of eNOS suppressed the increases in [NO]i and cell shortening. When both PI3K-Akt and cAMP-PKA signaling were inhibited, the Ucn2-induced increases in [NO]i and cell shortening were attenuated. Thus, in rabbit ventricular myocytes, Ucn2 causes activation of cAMP-PKA, PI3K-Akt, and MEK1/2-ERK1/2 signaling. The MEK1/2-ERK1/2 pathway is not required for stimulation of NO signaling in these cells. The other two pathways, cAMP-PKA and PI3K-Akt, converge on eNOS phosphorylation at Ser1177 and result in pronounced and sustained cellular NO production with subsequent stimulation of cGMP signaling. Copyright © 2014 the American Physiological Society.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic GMP - metabolism; Heart Ventricles - cytology Heart Ventricles - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myocytes, Cardiac - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation -; Proto-Oncogene Proteins c-akt - metabolism; Rabbits -; Receptors, Corticotropin-Releasing Hormone - metabolism; Serine - metabolism; Signal Transduction -; Urocortins - metabolism
Find related publications in this database (Keywords): urocortin; cardiac myocyte; eNOS phosphorylation; nitric oxide