Open AccessHypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia
Author(s) -
Ning Wang,
Xue Shi,
Shakil A. Khan,
Benjamin Wang,
Gregg L. Semenza,
Nanduri R. Prabhakar,
Jayasri Nanduri
Publication year - 2020
Publication title -
american journal of physiology. cell physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.432
H-Index - 181
eISSN - 1522-1563
pISSN - 0363-6143
DOI - 10.1152/ajpcell.00309.2020
Subject(s) - endocrinology , nox4 , medicine , intermittent hypoxia , downregulation and upregulation , hypoxia (environmental) , nadph oxidase , insulin , biology , chemistry , oxidative stress , obstructive sleep apnea , biochemistry , oxygen , organic chemistry , gene
The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1 -/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O 2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1 -/- mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H 2 O 2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H 2 O 2 contribute to IH-induced pancreatic β-cell dysfunction.