Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction

Kathryn J. Schunke, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA. kschunke@hawaii.edu.
Jeannette Rodriguez, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Jhansi Dyavanapalli, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA.
John Schloen, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Xin Wang, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA.
Joan Escobar, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA.
Grant Kowalik, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Emily C. Cheung, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Caitlin Ribeiro, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA.
Rebekah Russo, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Bridget R. Alber, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Olga Dergacheva, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA.
Sheena W. Chen, Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center, 50 Irving St. NW, Washington, DC, 20422, USA.
Alejandro E. Murillo-Berlioz, Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center, 50 Irving St. NW, Washington, DC, 20422, USA.
Kyongjune B. Lee, Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center, 50 Irving St. NW, Washington, DC, 20422, USA.
Gregory Trachiotis, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Emilia Entcheva, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA.
Christine A. Brantner, The GWU Nanofabrication and Imaging Center, 800 22nd Street NW, Washington, DC, 20052, USA.
David Mendelowitz, Department of Pharmacology and Physiology, George Washington University, Suite 640 Ross Hall, 2300 Eye St. NW, Washington, DC, 20052, USA. dmendel@gwu.edu.
Matthew W. Kay, Department of Biomedical Engineering, George Washington University, Suite 5000 Science and Engineering Hall, 800 22nd Street NW, Washington, DC, 20052, USA. phymwk@gwu.edu.

Document Type

Journal Article

Publication Date

10-6-2023

Journal

Basic research in cardiology

Volume

118

Issue

1

DOI

10.1007/s00395-023-01013-1

Keywords

Arrhythmia; Cardioprotection; Infarction; Mitochondria; Oxytocin; Parasympathetic nervous system

Abstract

Altered autonomic balance is a hallmark of numerous cardiovascular diseases, including myocardial infarction (MI). Although device-based vagal stimulation is cardioprotective during chronic disease, a non-invasive approach to selectively stimulate the cardiac parasympathetic system immediately after an infarction does not exist and is desperately needed. Cardiac vagal neurons (CVNs) in the brainstem receive powerful excitation from a population of neurons in the paraventricular nucleus (PVN) of the hypothalamus that co-release oxytocin (OXT) and glutamate to excite CVNs. We tested if chemogenetic activation of PVN-OXT neurons following MI would be cardioprotective. The PVN of neonatal rats was transfected with vectors to selectively express DREADDs within OXT neurons. At 6 weeks of age, an MI was induced and DREADDs were activated with clozapine-N-oxide. Seven days following MI, patch-clamp electrophysiology confirmed the augmented excitatory neurotransmission from PVN-OXT neurons to downstream nuclei critical for parasympathetic activity with treatment (43.7 ± 10 vs 86.9 ± 9 pA; MI vs. treatment), resulting in stark improvements in survival (85% vs. 95%; MI vs. treatment), inflammation, fibrosis assessed by trichrome blue staining, mitochondrial function assessed by Seahorse assays, and reduced incidence of arrhythmias (50% vs. 10% cumulative incidence of ventricular fibrillation; MI vs. treatment). Myocardial transcriptomic analysis provided molecular insight into potential cardioprotective mechanisms, which revealed the preservation of beneficial signaling pathways, including muscarinic receptor activation, in treated animals. These comprehensive results demonstrate that the PVN-OXT network could be a promising therapeutic target to quickly activate beneficial parasympathetic-mediated cellular pathways within the heart during the early stages of infarction.

Department

Pharmacology and Physiology

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