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Cardiomyocyte-derived small extracellular vesicles can signal eNOS activation in cardiac microvascular endothelial cells to protect against Ischemia/Reperfusion injury

Authors
  • Chen, Guihao1, 2
  • Xu, Chuansheng1
  • Gillette, Thomas G.2
  • Huang, Tongyi3
  • Huang, Peisen1
  • Li, Qing1
  • Li, Xiangdong1
  • Li, Qinfeng4
  • Ning, Yu1
  • Tang, Ruijie1
  • Huang, Cunrong1
  • Xiong, Yuyan1
  • Tian, Xiaqiu1, 5
  • Xu, Jun1
  • Xu, Junyan1
  • Chang, Liping6
  • Wei, Cong6, 7
  • Jin, Chen1
  • Hill, Joseph A.2
  • Yang, Yuejin1
  • 1 State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
  • 2 Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA
  • 3 Department of Medical Ultrasound, Institute of Diagnostic and Interventional Ultrasound, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
  • 4 Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310020, China
  • 5 Center for Cardiac Intensive Care, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China
  • 6 Yiling Hospital of Hebei Medical University, National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Shijiazhuang, Hebei 050035, China
  • 7 National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Key Laboratory of State Administration of TCM (Cardio-Cerebral Vessel Collateral Disease), Shijiazhuang, Hebei 050035, China
Type
Published Article
Journal
Theranostics
Publisher
Ivyspring International Publisher
Publication Date
Sep 23, 2020
Volume
10
Issue
25
Pages
11754–11774
Identifiers
DOI: 10.7150/thno.43163
PMID: 33052245
PMCID: PMC7546010
Source
PubMed Central
Keywords
License
Green

Abstract

Rationale: The crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs) has emerged as a key component in the development of, and protection against, cardiac diseases. For example, activation of endothelial nitric oxide synthase (eNOS) in CMECs, by therapeutic strategies such as ischemic preconditioning, plays a critical role in the protection against myocardial ischemia/reperfusion (I/R) injury. However, much less is known about the signals produced by CMs that are able to regulate CMEC biology. Here we uncovered one such mechanism using Tongxinluo (TXL), a traditional Chinese medicine, that alleviates myocardial ischemia/reperfusion (I/R) injury by activating CMEC eNOS. The aim of our study is to identify the signals produced by CMs that can regulate CMEC biology during I/R. Methods: Ex vivo, in vivo, and in vitro settings of ischemia-reperfusion were used in our study, with the protective signaling pathways activated in CMECs identified using genetic inhibition (p70s6k1 siRNA, miR-145-5p mimics, etc.), chemical inhibitors (the eNOS inhibitor, L-NNA, and the small extracellular vesicles (sEVs) inhibitor, GW4869) and Western blot analyses. TritonX-100 at a dose of 0.125% was utilized to inactivate the eNOS activity in endothelium to investigate the role of CMEC-derived eNOS in TXL-induced cardioprotection. Results: We found that while CMEC-derived eNOS activity was required for the cardioprotection of TXL, activation of eNOS in CMECs by TXL did not occur directly. Instead, eNOS activation in CMECs required a crosstalk between CMs and CMECs through the uptake of CM-derived sEVs. We further demonstrate that TXL induced CM-sEVs contain increased levels of Long Intergenic Non-Protein Coding RNA, Regulator Of Reprogramming (Linc-ROR). Upon uptake into CMECs, linc-ROR downregulates its target miR-145-5p leading to activation of the eNOS pathway by facilitating the expression of p70s6k1 in these cells. The activation of CMEC-derived eNOS works to increase survival in both the CMECs and the CMs themselves. Conclusions: These data uncover a mechanism by which the crosstalk between CMs and CMECs leads to the increased survival of the heart after I/R injury and point to a new therapeutic target for the blunting of myocardial I/R injury.

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