Protective effects of acetylcholine on hypoxia-induced endothelial-to-mesenchymal transition in human cardiac microvascu
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Protective effects of acetylcholine on hypoxia‑induced endothelial‑to‑mesenchymal transition in human cardiac microvascular endothelial cells Zhiyang Li1 · Xuelian Li2,3 · Yeqian Zhu4 · Qiushi Chen4 · Bingong Li2,3 · Fengxiang Zhang4,5 Received: 16 January 2020 / Accepted: 18 June 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Endothelial-to-mesenchymal transition (EndMT) has been reported as a key factor in myocardial fibrosis. Acetylcholine (ACh), a neurotransmitter of the vagus nerve, has been confirmed to exert cardio-protective properties with unclear mechanisms. In this study, the specific markers of cell injury, EndMT, inflammation, and autophagy were measured. We found that treatment with ACh prevented hypoxia-induced cell viability reduction and apoptosis in human cardiac microvascular endothelial cells (HCMECs). Additionally, our results indicate that pre-treatment with ACh significantly suppresses hypoxiainduced EndMT and NF-κB activation in HCMECs. ACh also reduced hypoxia-inducible factor (HIF)-1ɑ protein levels under hypoxia. Knock down of HIF-1ɑ enhanced the inhibitory effect of ACh on NF-κB activation. The NF-κB-specific small molecule inhibitor BAY 11-7082, prostaglandin E2, and LY294002 prevented hypoxia-induced EndMT. Moreover, our data show that hypoxia triggers autophagy in HCMECs, and ACh significantly upregulates autophagy activity. Pre-treatment of HCMECs with 3-methyladenine or chloroquine partially reversed ACh-induced EndMT inhibition. These results suggest that ACh may confer protection against hypoxia-induced EndMT through the inhibition of NF-κB and the induction of autophagy. Keywords Acetylcholine · Endothelial-to-mesenchymal transition · Hypoxia · Autophagy · NF-κb inhibition Abbreviations α-SMA α-Smooth muscle actin Ach Acetylcholine AMI Acute myocardial infarction ECM Extracellular matrix EMT Epithelial-to-mesenchymal transition EndMT Endothelial-to-mesenchymal transition Zhiyang Li, Xuelian Li, and Yeqian Zhu have contributed equally to this study.
HCAECs Human coronary artery endothelial cells HCMECs Human cardiac microvascular endothelial cells HUVECs Human umbilical vein endothelial cells MF Myocardial fibrosis PBS Phosphate buffered saline PECAM-1 Platelet endothelial cell adhesion molecule-1 TEM Transmission electron microscopy VE-cad Vascular endothelial cadherin
* Fengxiang Zhang [email protected]
1
Grade 2016 Class 2, The First School of Clinical Medicine, Nanjing Medical University, Nanjing 211166, China
Zhiyang Li [email protected]
2
Department of Cardiology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao 266011, China
Xuelian Li [email protected]
3
Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
Yeqian Zhu [email protected]
4
The Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 211166, China
5
Section of Pacing and Electrophysi
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