HIF‐1α Increases Glutamatergic NMDA receptors in the PVN during chronic heart failure

Abstract

Increased sympathetic outflow is a common feature of chronic heart failure (HF). Potentiation of glutamatergic tone (increase in N‐methyl‐D‐aspartate (NMDA)‐type1 (NR1) receptors expression) within the paraventricular nucleus (PVN) has been related to the increased sympathetic drive in HF. However, the underlying molecular mechanism(s) for the upregulation of NR1 remains unclear. Immunohistochemistry of the PVN of rats with HF (coronary artery ligation‐induced) revealed upregulation of Hypoxia‐Inducible‐Factor 1α (HIF‐1α) compared to Sham. We hypothesized that increased HIF‐1α may contributes to the augmentation of the NR1 expression in the PVN of rats with HF. Initially, using an in vitro neuronal cell line (NG108–15), we found 2‐fold increase in HIF‐1α expression after 12h of hypoxia treatment in chambers. Concomitantly, hypoxia also showed significant increases in NR1 mRNA at 4h (6.5 fold) and 8h (7.2 fold) and protein levels after 12h (40%). Silencing of HIF‐1α in NG108 neurons led to decrease in expression of NR1. Taking this in vitro data to the whole animal studies, HIF‐1α knockdown in the PVN of rats with HF ameliorated the increased sympathoexcitation to NMDA (57.4±5.3 vs. 27.0±1.3). Taken together, these results suggest a contributory role for HIF‐1α in the regulation of NR1 expression, providing a novel mechanistic insight for the modulation of sympathoexcitation induced by the PVN in HF.Supported by NIHHLS2222.