Effects of Varying Degrees of Intermittent Hypoxia on Proinflammatory Cytokines and Adipokines in Rats and 3T3-L1 Adipocytes

Abstract

ObjectivesIntermittent hypoxia (IH), resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA). IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR) is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status.MethodsWe developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-κB) DNA binding reactions, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (Glut-1), necrosis factor alpha (TNF-α), interleukin (IL) -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-α, IL-6, leptin and adiponectin levels were analyzed.ResultsThe insulin and blood glucose levels in rats and NF-κB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1α and Glut-1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-α, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin.ConclusionsOxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical relationships between OSA and IR.

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

“…It is known that as a part of adaptive response to hypoxia, there is upregulated expression of several genes encoding glycolytic enzymes. 27 However, to our best knowledge, an IHT-induced change in mRNA expression of these genes has not been reported prior to our current study. Our present results showed that whereas no significant difference in baseline expression of the examined genes between prediabetes and healthy subjects, the changes in HIF-1a-regulated gene expression in response to IHT was subsequent to those of HIF-1a mRNA in the healthy group and the maximum response was observed one month after the end of IHT (Figure 1(b) to (d)).…”

“…24,25 GLUT-1 is upregulated under hypoxia, and its activity depends of the severity of hypoxic impact. 26,27 Another HIF-1a target gene important for glucose homeostasis is insulin receptor (INSR). Insulin exerts its physiological effects through this member of tyrosine kinase family of transmembrane signaling proteins encoded by a single gene INSR.…”

Lymphocytes from intermittent hypoxia-exposed rats increase the apoptotic signals in endothelial cells via oxidative and inflammatory injury in vitro

“…RAECs grown in culture plates were placed in Plexiglas exposure chamber and exposed to IH conditions for 5 h. Consequently, RAECs were cocultured with lymphocytes with IH or air for another 4 h at the ratio of lymphocytes/endothelial cells 10:1. The hypoxia exposure protocol for cell incubation was similar with that reported in our previous study [16].…”

Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

“…All rats were randomly allocated to six groups (n = 5 each): A. normoxia control group (NC); B. chloroquine treatment group (CQ), intraperitoneal injection of chloroquine (60 mg/kg/day); C. rapamycin treatment group (RA), intraperitoneal injection of rapamycin (0.5 mg/kg/day); D. IH group (IH); E. IH and chloroquine treatment group (IH+CQ), intraperitoneal injection of chloroquine (60 mg/kg/day) prior to IH exposure; and F. IH and rapamycin treatment group (IH+RA), intraperitoneal injection of rapamycin (0.5 mg/kg/day) prior to IH exposure. The IH animal model was established according to the procedures described by He et al [17].. Briefly, model rats were exposed to IH for 6 weeks, 8 h/day (9 AM to 5 PM) in a specialized Plexiglas chamber.…”