Biochemical and Biophysical Research Communications, Vol.438, No.3, 507-512, 2013
MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria
Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are pivotal and intensively studied signaling pathways in hypoxic conditions. However, the roles of MAPK and PI3K in the regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion are not well understood. The purpose of the present study was to investigate the mechanism by which the MAPK/ERK (extracellular signal-regulated kinase) and PI3K signaling pathways regulate the acute hypoxia-induced ANP secretion in isolated beating rabbit atria. An acute hypoxic perfused beating rabbit atrial model was used. The ANP levels in the atrial perfusates were measured by radioimmunoassay, and the hypoxia-inducible factor-1 alpha (HIF-1 alpha) mRNA and protein levels in the atrial tissue were determined by RT-PCR and Western blot. Acute hypoxia significantly increased ANP secretion and HIF-1 alpha mRNA and protein levels. Hypoxia-induced ANP secretion was markedly attenuated by the HIF-1 alpha inhibitors, rotenone (0.5 mu mol/L) and CAY10585 (10 mu mol/L), concomitantly with downregulation of the hypoxia-induced HIF-1 alpha mRNA and protein levels. PD098059 (30 mu mol/L) and LY294002 (30 mu mol/L), inhibitors of MAPK and PI3K, markedly abolished the hypoxia-induced ANP secretion and atrial HIF-1 alpha mRNA and protein levels. The hypoxia-suppressed atrial dynamics were significantly attenuated by PD098059 and LY294002. Acute hypoxia in isolated perfused beating rabbit atria, markedly increased ANP secretion through HIF-1 alpha upregulation, which was regulated by the MAPK/ERK and PI3K pathways. ANP appears to be part of the protective program regulated by HIF-1 alpha in the response to acute hypoxic conditions. (C) 2013 Elsevier Inc. All rights reserved.