急性心肌梗死后下丘脑催产素神经元驱动的心脏保护的结果。

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2023-10-06 DOI:10.1007/s00395-023-01013-1
Kathryn J Schunke, Jeannette Rodriguez, Jhansi Dyavanapalli, John Schloen, Xin Wang, Joan Escobar, Grant Kowalik, Emily C Cheung, Caitlin Ribeiro, Rebekah Russo, Bridget R Alber, Olga Dergacheva, Sheena W Chen, Alejandro E Murillo-Berlioz, Kyongjune B Lee, Gregory Trachiotis, Emilia Entcheva, Christine A Brantner, David Mendelowitz, Matthew W Kay
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引用次数: 0

摘要

自主神经平衡的改变是许多心血管疾病的标志,包括心肌梗死(MI)。尽管基于设备的迷走神经刺激在慢性病期间具有心脏保护作用,但在梗死后立即选择性刺激心脏副交感神经系统的非侵入性方法并不存在,而且是迫切需要的。脑干中的心脏迷走神经神经元(CVNs)从下丘脑室旁核(PVN)中的一群神经元获得强大的兴奋,这些神经元共同释放催产素(OXT)和谷氨酸来刺激CVNs。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,在OXT神经元内选择性表达DREADDs。在6周龄时,诱导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,PVN-OXT神经元向下游核的兴奋性神经传递增强,这对治疗副交感神经活动至关重要(43.7 ± 10对86.9 ± 9pA;MI与治疗),导致存活率(85%与95%;MI与治疗相比)、炎症、三色蓝染色评估的纤维化、海马分析评估的线粒体功能以及心律失常发生率降低(心室颤动累计发生率50%与10%;MI与处理相比)的显着改善。心肌转录组学分析为潜在的心脏保护机制提供了分子见解,揭示了在治疗动物中保存有益的信号通路,包括毒蕈碱受体激活。这些综合结果表明,PVN-OXT网络可能是一个很有前途的治疗靶点,可以在梗死早期快速激活心脏内有益的副交感神经介导的细胞通路。
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Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction.

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.

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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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