Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure.
BACKGROUND
Increased sympathetic outflow is a major contributor to the progression of chronic heart failure (CHF). Potentiation of glutamatergic tone has been causally related to the sympathoexcitation in CHF. Specifically, an increase in the N-methyl-d-aspartate-type 1 receptor (NMDA-NR1) expression within the paraventricular nucleus (PVN) is critically linked to the increased sympathoexcitation during CHF. However, the molecular mechanism(s) for the upregulation of NMDA-NR1remains unexplored. We hypothesized that hypoxia via hypoxia-inducible factor 1α (HIF-1α) might contribute to the augmentation of the NMDA-NR1-mediated sympathoexcitatory responses from the PVN in CHF.


RESULTS
Immunohistochemistry staining, mRNA, and protein for hypoxia-inducible factor 1α were upregulated within the PVN of left coronary artery-ligated CHF rats. In neuronal cell line (NG108-15) in vitro, hypoxia caused a significant increase in mRNA and protein for HIF-1α (2-fold) with the concomitant increase in NMDA-NR1mRNA, protein levels, and glutamate-induced Ca+influx. Chromatin immunoprecipitation assay identified HIF-1α binding to NMDA-NR1promoter during hypoxia. Silencing of HIF-1α in NG108 cells leads to a significant decrease in expression of NMDA-NR1, suggesting that expression of HIF-1α is necessary for the upregulation of NMDA-NR1. Consistent with these observations, HIF-1α silencing within the PVN abrogated the increased basal sympathetic tone and sympathoexcitatory responses to microinjection of NMDA in the PVN of rats with CHF.


CONCLUSIONS
These results uncover a critical role for HIF-1 in the upregulation of NMDA-NR1to mediate sympathoexcitation in CHF. We conclude that subtle hypoxia within the PVN may act as a metabolic cue to modulate sympathoexcitation during CHF.
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Neeru M
NM
Sharma
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Craig J
CJ
Cunningham
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Hong
H
Zheng
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Xuefei
X
Liu
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha. kpatel@unmc.edu.
Kaushik P
KP
Patel
D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D015854:Up-Regulation
D018690:Excitatory Amino Acid Agonists; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C409466:NR1 NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate
NMDA receptors; hypoxia-inducible factor 1; myocardial ischemia; paraventricular nucleus