Effect Of HIF-1α On Hypoxia-induced Atrial ANP Secretion

The heart not only as a pumping blood organ but also as an endocrine gland, because the heart has been shown to synthesis and secretes natiruretic peptides. The family of natriuretic peptides (NPs) involving several members such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis natriuretic peptide (DNP). The NPs are involved in the natriuresis, water and electrolytic balance, regulation of blood pressure and sustaining homeostasis.ANP, the first member of the NPs, is synthesis and release in the atrial myocytes. Natriuretic peptide receptors (NPRs) involving NPR-A, NPR-B and NPR-C. These receptors are existed in various tissues such as cardiovascular and central nervous system, lymphatic tissue, reproductive organ, and kidney. It is demonstrated that ANP has been participated in the vascular relaxation, down regulation of blood pressure, suppression of cellular proliferation, regulation of immunifaction, protective cells and lipolysis. Many factors are closely related to the regulation of atrial ANP secretion, such as atrial dynamics, humoral and neural factors, hypoxia as well as ischemia, hypertonic solution, and hyperkalemia. Endothelin-1(ET-1), angiotensin II, glucocorticosteroid, antidiuretic hormone (vasopressin) and prostaglandin are also increased atrial ANP secretion. But the nitric oxide (NO) has been shown to decreased ANP release. In addition, adrenergic, cholinergic and peptidergic receptors are also correlated in the regulation of ANP secretion. However, atrial stretch is the critical factor in regulation of ANP secretion.In the1986, it is demonstrated that hypoxia is the most stimulator of the ANP secretion in vitro and in vivo models. However, the mechanisms by which hypoxia stimulates ANP secretion is not well known. Hypoxic pathway is induced with activation of the hypoxia-inducible factor-1(HIF-1) transcription which has been known to present in almost cell types. It has been tightly regulated by O2availability and regulates the expression of numerous hypoxic genes. HIF-1is discovered by Semenza et al., and it is demonstrated that HIF-1is a heterodimer containing HIF-la and HIF-1β subunit. HIF-la is closely regulated by cellular O2concentration and regulates ANP gene transcription and the expression of ANP promoters.Endothelin-1(ET-1), which is discovered by Yanagisawa et al., in the1988, is a potent vasoactive peptide of21amino acids that was originally isolated from a culture medium of porcine aortic endothelial cells. It has been demonstrated that ET-1plays a crucial role in the regulation of cardiovascular function in various cardiovascular disorders. There are three isomers of endothelin (ET) such as ET-1, ET-2and ET-3. ET receptors have been identified of two seven-transmembrane G protein-coupled endothelin receptors, endothelin A (ETA) and endothelin B (ETB) receptor.Numerous studies have been demonstrated that hypoxia stimulates cardiac ET-1secretion and its gene expression and the ET-1has been shown to increase the HIF-1gene transcription. Whitman et al., reported that over expression of HIF-1may stimulates ET-1secretion and its gene expression. In the normoxia conditions, HIF-la expression is increased by epidermal Growth Factor (EGF) and insulin-like growth factor (IGF) via activation of phosphatidylinositol-3-kinase (PI3K)/protein serine threonine kinases (Akt). However, effects of HIF-la and the PI3K signaling pathway on hypoxia-increased atrial ANP secretion are not well known.Therefore, the purpose of the present study is to investigate the effects of HIF-1α, hypoxia-induced endogenous ET-1and PI3K signaling pathway on the regulation of ANP secretion in isolated perfused beating rabbit atria.The data of the present study showed that,1. Acute hypoxia significantly increased atrial ANP as well as ET-1secretion (P<0.001vs control period respectively) and decreased in atrial stroke volume (P<0.001vs control period).2. BQ123(0.3μmol/L), a blocker of ETA receptor, or BQ788(0.3μmol/L), an antagonist of ETB receptor, partially attenuated hypoxia-increased atrial ANP secretion (P<0.001vs control period respectively); inhibitory effect of BQ123+BQ788was stronger than BQ123or BQ788(P<0.001vs BQ123or BQ788alone).3. A PI3k inhibitor LY294002(3.0μmol/L) also attenuated the hypoxia-increased atrial ANP (P<0.001vs control) and ET-1secretion (P<0.01vs control).4. Inhibitory effect of LY294002+BQ123+BQ788was stronger than LY294002or BQ123+BQ788alone (P<0.001vs LY294002or BQ123+BQ788alone).5. A HIF-la inhibitor rotenone (50.0μmol/L) blocked the hypoxia-increased ANP secretion completely (P>0.05vs control).Results of the present study indicated that,1. HIF-la has been shown to regulated hypoxia-increased atrial ANP secretion involving the important role of PI3K signaling pathway.2. Hypoxia-induced endogenous ET-1partially involved in the regulation of hypoxia-increased ANP secretion in beating rabbit atria.