Src-IL-18 signaling regulates the secretion of atrial natriuretic factor in hypoxic beating rat atria
Abstract
Background: Interleukin (IL)-18 is produced mainly in the heart and can be associated with the development
of cardiac hypertrophy that leads to cardiac dysfunction. However, the effects of hypoxia on
IL-18 expression and atrial natriuretic factor (ANF) secretion remain largely unknown.
Aim: The aim of this study was to assess the effect of hypoxia on IL-18 production and its role in ANF
secretion by using an isolated perfused beating rat atrial model.
Methods: The level of ANF in the perfusates was determined by radioimmunoassay, and the protein
levels of Src, IL-18 and its receptors (IL-18-Rα and IL-18-Rβ), Rho guanine nucleotide exchange factor
(RhoGEF) and RhoA, activating transcription factor 3 (ATF3), T cell factor (TCF) 3 and 4, and lymphoid
enhancer factor (LEF) 1 in atrial tissue samples were detected by Western blotting.
Results: Hypoxia significantly upregulated the expression of the non-receptor tyrosine kinase Src, and
this effect was blocked by endothelin-1 receptor type A (BQ123) and type B (BQ788) antagonists. Hypoxia
also enhanced the expression of RhoGEF and RhoA concomitantly with the upregulation of
IL-18, IL-18-Rα and IL-18-Rβ. The hypoxia-induced RhoGEF and RhoA were abolished by Src inhibitor
1 (SrcI), and the protein levels of IL-18 and its two receptors were also blocked by SrcI. Moreover, the
hypoxia-induced expression levels of ATF3, TCF3, TCF4 and LEF1 were repealed by IL-18 binding protein,
and the hypoxia-promoted secretion of ANF was also obviously attenuated by this binding protein.
Conclusions: These findings imply that Src-IL-18 signaling is involved in the release of ANF in hypoxic
beating rat atria.
Keywords: atrial natriuretic factorendothelin-1hypoxiainterleukin-18non-receptor tyrosine kinase Src
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