Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury

Xiaohao Zhang; Pengyu Gong; Ying Zhao; Ting Wan; Kang Yuan; Yunyun Xiong; Min Wu; Mingming Zha; Yunzi Li; Teng Jiang; Xinfeng Liu; Ruidong Ye; Yi Xie; Gelin Xu

EBioMedicine (Oct 2022)

Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury

Xiaohao Zhang,
Pengyu Gong,
Ying Zhao,
Ting Wan,
Kang Yuan,
Yunyun Xiong,
Min Wu,
Mingming Zha,
Yunzi Li,
Teng Jiang,
Xinfeng Liu,
Ruidong Ye,
Yi Xie,
Gelin Xu

Affiliations

Xiaohao Zhang: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China; Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China; Department of Neurology, Jiangsu Provincial Second Chinese Medicine Hospital, Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, China
Pengyu Gong: Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226000, China
Ying Zhao: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Ting Wan: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Kang Yuan: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Yunyun Xiong: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing 100070, China; Chinese Institute for Brain Research, Beijing 100070, China
Min Wu: Department of Neurology, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China
Mingming Zha: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Yunzi Li: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Teng Jiang: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, China
Xinfeng Liu: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Ruidong Ye: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China
Yi Xie: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China; Corresponding authors at: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Rd, Nanjing, Jiangsu 210000, China.
Gelin Xu: Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China; Corresponding authors at: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Rd, Nanjing, Jiangsu 210000, China.

Journal volume & issue: Vol. 84
p. 104275

Abstract

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Summary: Background: Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation. Methods: The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors. Findings: Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1−/− endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1−/− tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction. Interpretation: Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion. Funding: This work was supported by National Natural Science Foundation of China.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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