Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl- d -Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure

Abstract

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-NR 1 ) 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-NR 1 remains unexplored. We hypothesized that hypoxia via hypoxia-inducible factor 1α (HIF-1α) might contribute to the augmentation of the NMDA-NR 1 –mediated sympathoexcitatory responses from the PVN in CHF. Methods and 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-NR 1 mRNA, protein levels, and glutamate-induced Ca + influx. Chromatin immunoprecipitation assay identified HIF-1α binding to NMDA-NR 1 promoter during hypoxia. Silencing of HIF-1α in NG108 cells leads to a significant decrease in expression of NMDA-NR 1 , suggesting that expression of HIF-1α is necessary for the upregulation of NMDA-NR 1 . 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-NR 1 to mediate sympathoexcitation in CHF. We conclude that subtle hypoxia within the PVN may act as a metabolic cue to modulate sympathoexcitation during CHF.