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

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.

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

“…M muscarinic receptor activation has been shown to improve cardiac function in various heart diseases 72 , 73 . Additionally, recent research has included muscarinic receptor activation as a potential cardiac beneficial signaling pathway in the analysis of myocardial transcriptomics in mice with myocardial infarction 74 . Therefore, we speculate that the protective effect of Sema in myocardium remodeling may also be related to the activation of M muscarinic receptors.…”

Sex differences in cardiac transcriptomic response to neonatal sleep apnea

“…Echocardiographic measurements were taken 2 days before sacrifice on lightly anesthetized (1.5% isoflurane inhalation) rats using the Visualsonics small‐animal system (Vevo 3100 Imaging System, FUJIFILM Visual Sonics Inc, Toronto, Ontario, Canada), as described previously (Dyavanapalli et al., 2020 ; Schunke et al., 2023 ). LV outflow tract diameter was measured from a 2D‐parasternal LV long axis view.…”