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Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure.
Circ Heart Fail. 2016 Nov; 9(11)CH

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-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-NR1 remains 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.

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-NR1 mRNA, protein levels, and glutamate-induced Ca+ influx. Chromatin immunoprecipitation 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 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-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.

Authors+Show Affiliations

From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha. kpatel@unmc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27810863

Citation

Sharma, Neeru M., et al. "Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation Via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure." Circulation. Heart Failure, vol. 9, no. 11, 2016.
Sharma NM, Cunningham CJ, Zheng H, et al. Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure. Circ Heart Fail. 2016;9(11).
Sharma, N. M., Cunningham, C. J., Zheng, H., Liu, X., & Patel, K. P. (2016). Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure. Circulation. Heart Failure, 9(11).
Sharma NM, et al. Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation Via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure. Circ Heart Fail. 2016;9(11) PubMed PMID: 27810863.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure. AU - Sharma,Neeru M, AU - Cunningham,Craig J, AU - Zheng,Hong, AU - Liu,Xuefei, AU - Patel,Kaushik P, PY - 2016/07/07/received PY - 2016/10/13/accepted PY - 2016/11/5/pubmed PY - 2019/3/21/medline PY - 2016/11/5/entrez KW - NMDA receptors KW - hypoxia-inducible factor 1 KW - myocardial ischemia KW - paraventricular nucleus JF - Circulation. Heart failure JO - Circ Heart Fail VL - 9 IS - 11 N2 - 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-NR1 remains 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. 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-NR1 mRNA, protein levels, and glutamate-induced Ca+ influx. Chromatin immunoprecipitation 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 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-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. SN - 1941-3297 UR - https://www.unboundmedicine.com/medline/citation/27810863/Hypoxia_Inducible_Factor_1α_Mediates_Increased_Sympathoexcitation_via_Glutamatergic_N_Methyl_d_Aspartate_Receptors_in_the_Paraventricular_Nucleus_of_Rats_With_Chronic_Heart_Failure_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.116.003423?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -