期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 307, 期 5, 页码 H689-H700出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00694.2013
关键词
urocortin; cardiac myocyte; eNOS phosphorylation; nitric oxide
资金
- Deutsche Forschungsgemeinschaft [MA 1982/4-2, TPA03 SFB 1002]
- Early Career Fellowship from the National Health and Medical Research Council of Australia
- Ernst und Berta Grimmke-Stiftung
- Fondation Leducq
- Max-Planck-Society, SNRP2 [5U54NS039406-9]
- National Heart, Lung, and Blood Institute [R01-HL-062231, P01-HL-080101, R01-HL-101235]
- Leducq Foundation
- Shanghai Pujiang Program [10PJ1406900]
- State of Styria grant
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.
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