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.

自主神经平衡改变是许多心血管疾病的标志，包括心肌梗塞 (MI)。尽管基于设备的迷走神经刺激在慢性疾病期间具有心脏保护作用，但在梗塞后立即选择性刺激心脏副交感系统的非侵入性方法还不存在，而且是迫切需要的。脑干中的心脏迷走神经元 (CVN) 接收来自下丘脑室旁核 (PVN) 中的一群神经元的强烈兴奋，这些神经元共同释放催产素 (OXT) 和谷氨酸以兴奋 CVN。我们测试了 MI 后 PVN-OXT 神经元的化学遗传学激活是否具有心脏保护作用。用载体转染新生大鼠的 PVN，以在 OXT 神经元内选择性表达 DREADD。 6 周龄时，诱发 MI，并用氯氮平-N-氧化物激活 DREADD。 MI 后 7 天，膜片钳电生理学证实治疗后从 PVN-OXT 神经元到对副交感神经活动至关重要的下游核的兴奋性神经传递增强（43.7 ± 10 vs 86.9 ± 9 pA；MI 与治疗），从而导致生存率显着改善（85% vs. 95%；MI vs. 治疗）、通过三色蓝染色评估炎症、纤维化、通过 Seahorse 测定评估线粒体功能，以及降低心律失常发生率（心室颤动累积发生率 50% vs. 10%；MI vs. 。 治疗）。心肌转录组分析提供了对潜在心脏保护机制的分子洞察，揭示了治疗动物中有益信号通路的保留，包括毒蕈碱受体激活。这些综合结果表明，PVN-OXT 网络可能是一个有前途的治疗靶点，可在梗塞早期阶段快速激活心脏内有益的副交感神经介导的细胞通路。