The protein tyrosine kinase inhibitor genistein suppresses hypoxia-induced atrial natriuretic peptide secretion mediated by the PI3K/Akt-HIF-1α pathway in isolated beating rat atria.

Abstract

Genistein, an isoflavonoid that can inhibit protein tyrosine kinase (PTK) phosphorylation, has been shown to play pivotal roles in the signal transduction pathways of hypoxic disorders. In this study, we established a rat model of isolated beating atrium and investigated the regulator role of genistein and its downstream signaling pathways in acute hypoxia-induced atrial natriuretic peptide (ANP) secretion. Radioimmunoassay was used to detect the ANP content in the atrial perfusates. Western blot analysis was used to determine the protein level of hypoxia-inducible factor 1α (HIF-1α), and GATA4 in the atrial tissue. The results showed that acute hypoxia substantially promoted ANP secretion, whereas this effect was partly attenuated by the PTKs inhibitor genistein (3 μM). By Western blotting analysis, we found that hypoxia-induced increase in phosphorylation of Akt and transcriptional factors, including HIF-1α, were also reversed by genistein. The perfused HIF-1α inhibitors rotenone (0.5 μM) or CAY10585 (10 μM) plus genistein significantly abolished the enhanced ANP section induced by hypoxia. Additionally, the perfused PI3K/Akt agonist insulin-like growth factor 1 (30 μM) also abolished ANP secretion induced by genistein and inhibited expression of HIF-1α. In summary, our data suggested that acute hypoxia markedly increased ANP secretion by PTKs through the phosphoinositide-3 kinase (PI3K)/HIF-1α dependent pathway.

• Authors: Qiu-Li Zhang, Ping Li, Lan Hong, Rui-Zhuang Li, Jia-Qi Wang, Xun Cui
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 99 Issue 11 Pg. 1184-1190 (Nov 2021) ISSN: 1205-7541 [Electronic] Canada
• PMID: 34612711 (Publication Type: Journal Article)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Protein Kinase Inhibitors
• Atrial Natriuretic Factor
• Genistein
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Atrial Natriuretic Factor (metabolism)
• Genistein (pharmacology)
• Heart Atria (metabolism)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• In Vitro Techniques
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (genetics, physiology)
• Rats