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-type1 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 up-regulation of NMDA-NR1 remains unexplored. We hypothesized that hypoxia via HIF-1α might contribute to the augmentation of the NMDA-NR1 mediated sympathoexcitatory responses from the PVN in CHF. Methods and Results Immunohistochemistry staining, mRNA, and protein for hypoxia-inducible-factor 1α (HIF-1α) were up-regulated 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 as well as protein for HIF-1α (2-fold) with the concomitant increase in NMDA-NR1 mRNA, protein levels, as well as glutamate-induced Ca+ influx. ChIP assay identified HIF-1α binding to NMDA-NR1 promoter 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 as well as 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 up-regulation of NMDA-NR1 to mediate sympathoexcitation in CHF. We conclude that subtle hypoxia within the PVN may act as a metabolic cue to modulate sympathoexcitation during CHF.

GLP-1 mediated diuresis and natriuresis are blunted in heart failure and restored by selective afferent renal denervation

“…We have shown that basal ARNA was higher in HF than Sham consistent with our previous report [26] as well as basal RSNA [29,32,33]. Intrapelvic injection of GLP-1 increased ARNA and this response was 1.5-fold greater in HF compared to Sham.…”

“…This anesthetic is specifically chosen to minimize the effects of anesthesia on central pathways involved in autonomic regulation of the cardiovascular system. Under this anesthesia a lot of the autonomic reflex functions are studied and are operational [24,26,29,[31][32][33] and therefore being used in current study examining effects of GLP-1 on neural circuitry of renal nerve activity involved in central nervous system. Body temperature was controlled at 36-38 °C by a stage heater.…”

Memantine, an NMDA Receptor Antagonist, Prevents Thyroxin-induced Hypertension, but Not Cardiac Remodeling

“…34 In the vein of thyroid hormone, NMDA-R activation has been linked to some kind of circulatory diseases, such as heart failure, cardiac arrhythmias and hypertension. [6][7][8][9][10] Therefore, it is rational to assume that the NMDA-R could be a prospective intervention target for the T4-induced cardiovascular changes and we believe that this is the first study to examine this hypothesis.…”

“…50 Additionally, it has been reported that memantine could prevent the reduction in the rat LV cardiomyocyte nuclear size induced by cold stress, which has been suggested to either initiate or increase the rodent cardiovascular dysfunction, 51,52 concluding that memantine might be a promising cardioprotective medication. 51 Actually, NMDA-R has been shown to play a key role in the induction of several heart failure/decreased cardiac contractility related pathways, such as the sympathoexcitation, 6,7 oxidative stress, calcium overload, cardiomyocyte apoptosis, 1,53 myocardial fibrosis 8 and stimulation of myocyte mitochondrial matrix metalloproteinase. 11 Even though T4-induced cardiac remodeling has been referred to similar mechanisms, including the sympathetic nervous system, 54 oxidative stress, 19,20 cardiomyocyte apoptosis 21 and matrix metalloproteinase, 22 memantine could not inhibit any of the T4-induced cardiac pathological manifestations in the current study.…”

“…The ionotropic receptors are differentiated into three subtypes in proportion to their explicit agonists: the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R), kainite receptor (KA-R) and NMDA-R. 1,2 Although NMDA-R expression is well-known for the central nervous system, its expression has been also demonstrated in peripheral organs, including the cardiomyocytes 3,4 and endothelial cells. 5 Interestingly, NMDA-R activation has been causally associated with myocardial pathogenesis, such as heart failure, 6,7 ventricular arrhythmias 8 and atrial fibrillation, 9 in addition to systemic hypertension. 10 These cardiac pathologies evoked by the activation of NMDA-R were attributed to increased oxidative stress, calcium overload, cardiomyocyte apoptosis, 1 myocardial fibrosis 8 and stimulation of myocyte mitochondrial matrix metalloproteinase.…”