Reactive oxygen species-dependent endothelin signaling is required for augmented hypoxic sensory response of the neonatal carotid body by intermittent hypoxia.
We previously reported that intermittent hypoxia (IH) augments hypoxic sensory response (HSR) and increases the number of glomus cells in neonatal carotid bodies. In the present study, we tested the hypothesis that recruitment of endothelin-1 (ET-1) signaling by reactive oxygen species (ROS) plays a critical role in IH-evoked changes in neonatal carotid bodies. Experiments were performed on neonatal rats exposed either to 10 days of IH (P0-P10; 8 h/day) or to normoxia. IH augmented HSR of the carotid bodies ex vivo and resulted in hyperplasia of glomus cells. The effects of IH were associated with enhanced basal release of ET-1 under normoxia, sensitization of carotid body response to exogenous ET-1, and upregulation of ET(A) but not an ET(B) receptor mRNA without altering the ET-1 content. An ET(A) but not ET(B) receptor antagonist prevented augmented HSR by IH. ROS levels were elevated in carotid bodies from IH-treated rat pups as evidenced by increased levels of malondialdehyde. Systemic administration of manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 5 mg/kg ip), a scavenger of O(2)(*-), prevented IH-induced elevation of ROS, basal release of ET-1, upregulation of ET(A) mRNA, and augmented HSR. In striking contrast, MnTMPyP treatment had no significant effect on IH-induced hyperplasia of glomus cells. These results demonstrate that IH-evoked increase in HSR involve a ROS-mediated increase in basal ET-1 release and upregulation of ET(A) receptor mRNA.
Pawar
Anita
A
Center for Systems Biology of O2 Sensing, Dept. of Medicine, The Univ. of Chicago, IL 60637, USA.
Nanduri
Jayasri
J
Yuan
Guoxiang
G
Khan
Shakil A
SA
Wang
Ning
N
Kumar
Ganesh K
GK
Prabhakar
Nanduri R
NR
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002344:Carotid Body / Q000502:physiology*; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D016232:Endothelins / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D008315:Malondialdehyde / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D019332:Endothelin-1; D016232:Endothelins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D008315:Malondialdehyde