Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia

摘要: Sleep disordered breathing with recurrent apnea (transient, repetitive cessation of breathing) is a major cause morbidity and mortality in adult humans (Nieto et al., 2000) pre-term infants (Poets 1994). Recurrent apneas are associated periodic decreases arterial blood oxygen or intermittent hypoxia (IH). Humans rodents exposed to IH exhibit autonomic morbidities including persistent sympathetic activation, hypertension, elevated circulating catecholamines (Narkiewicz Somers, 1997; Peppard 2000; Prabhakar Kumar, 2010). Studies on 1997) rodent models (Fletcher 1992; Peng 2006) have shown that the carotid body, which primary chemoreceptor for detecting changes PO2, responds by triggering reflex activation nervous system enhanced catecholamine secretion from adrenal medullary chromaffin cells (AMC), leading pressure (Bao Kumar 2006; Souvannakitti 2009). increases levels reactive species (ROS) body (Peng 2003) medulla (Kumar Anti-oxidant treatment prevents increased function 2003; Prabhakar, 2004; Del Rio 2010), augmented AMC Kuri 2007; 2009), Troncoso Brindeiro 2007), indicating ROS signaling critical cellular mechanism underlying IH-evoked morbidities. NADPH oxidase (Nox) activity source (Bedard Krause, 2007). leads expression several Nox isoforms (Souvannakitti central (CNS; Zhan 2005) as well cultured PC12 rat pheochromocytoma cells, derived (Yuan 2008). Of various isoforms, Nox2 has been implicated mediating effects sleep behavior (Zhan 2005). However, mechanisms gene response not elucidated. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) master regulator O2 homeostasis controls multiple physiological processes regulating hundreds genes (Mole 2009; Semenza, HIF-1 heterodimeric protein composed constitutively expressed HIF-1β subunit an O2-regulated HIF-1α (Wang 1995). We previously reported cell cultures 2005, 2008) mice 2006). In catecholamine-producing induction requires ROS-dependent phospholipase Cγ (PLCγ), kinase C (PKC), mammalian target rapamycin (mTOR; Yuan Physiological studies wild-type (WT) revealed striking morbidities, heightened activity, plasma catecholamines, exaggerated hypoxic ventilatory response, hypertension contrast, littermate Hif1a+/− mice, heterozygous null [knockout (KO)] allele at locus encoding HIF-1α, do display any these IH-induced responses Furthermore, were significantly CNS IH-exposed WT but Taken together, results indicated further generation, thereby creating feed-forward essential pathogenesis cardiovascular respiratory abnormalities. Establishing molecular generation next step understanding pathobiology IH. Based observations described above, we tested hypothesis IH, gene.