An Essential role for DeltaFosB in the median preoptic nucleus in the sustained hypertensive effects of chronic intermittent hypoxia.
One of the main clinical features of obstructive sleep apnea is sustained hypertension and elevated sympathetic activity during waking hours. Chronic intermittent hypoxia (CIH), animal model of the hypoxemia associated with obstructive sleep apnea, produces a similar sustained increase in blood pressure. This study determined the role of ΔFosB in the median preoptic nucleus (MnPO) in the sustained increase in mean arterial pressure associated with CIH. Rats were injected in the MnPO with viral vectors that expressed green fluorescent protein alone or green fluorescent protein plus a dominant-negative construct that inhibits the transcriptional effects of ΔFosB. In green fluorescent protein-injected rats and uninjected controls, 7-day exposure to CIH increased mean arterial pressure by 7 to 10 mm Hg during both intermittent hypoxia exposure and normoxia. Dominant-negative inhibition of MnPO ΔFosB did not affect changes in mean arterial pressure during intermittent hypoxia exposure but significantly reduced the sustained component of the blood pressure response to CIH during the normoxic dark phase. Inhibition of MnPO ΔFosB reduced the FosB/ΔFosB staining in the paraventricular nucleus and rostral ventrolateral medulla but not the nucleus of the solitary tract. PCR array analysis identified 6 activator protein 1-regulated genes expressed in the MnPO that were increased by CIH exposure, ace, ace2, nos1, nos3, prdx2, and map3k3. Dominant-negative inhibition of ΔFosB in the MnPO blocked increased expression of each of these genes in rats exposed to CIH except for Prdx2. ΔFosB may mediate transcriptional activity in MnPO necessary for sustained CIH hypertension, suggesting that neural adaptations may contribute to diurnal hypertension in obstructive sleep apnea.
Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA. Tom.Cunningham@unthsc.edu
J Thomas
JT
Cunningham
W David
WD
Knight
Steven W
SW
Mifflin
Eric J
EJ
Nestler
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002908:Chronic Disease; D000229:Dependovirus / Q000235:genetics; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D054464:Peroxiredoxins / Q000235:genetics; D011301:Preoptic Area / Q000378:metabolism / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D049452:Green Fluorescent Proteins; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2