Walther, Stefanie and Pluteanu, Florentina and Renz, Susanne and Nikonova, Yulia and Maxwell, Joshua T. and Yang, Li-Zhen and Schmidt, Kurt and Edwards, Joshua N. and Wakula, Paulina and Groschner, Klaus and Maier, Lars S. and Spiess, Joachim and Blatter, Lothar A. and Pieske, Burkert and Kockskaemper, Jens (2014) Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 307 (5). H689-H700. ISSN 0363-6135, 1522-1539
Full text not available from this repository. (Request a copy)Abstract
Urocortin 2 (Ucn2) is a cardioactive peptide exhibiting beneficial effects in normal and failing heart. In cardiomyocytes, it elicits cAMP-and Ca2+-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CARDIAC MYOCYTES; REPERFUSION INJURY; ENDOTHELIAL-CELLS; CA2+ RELEASE; CYCLIC-GMP; ACTIVATION; KINASE; CAMP; RECEPTORS; CALCIUM; urocortin; cardiac myocyte; eNOS phosphorylation; nitric oxide |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Aug 2019 11:07 |
| Last Modified: | 29 Aug 2019 11:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9677 |
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