miR-513c-5p Suppression Aggravates Pyroptosis of Endothelial Cell in Deep Venous Thrombosis by Promoting Caspase-1

Chu Chu; Bin Wang; Zhen Zhang; Wen Liu; Shangwen Sun; Gang Liang; Xiaoshan Zhang; Hongqiang An; Ran Wei; Xiaoxiao Zhu; Qiang Guo; Lin Zhao; Xiaoxiao Fu; Ke Xu; Xia Li

doi:10.3389/fcell.2022.838785

miR-513c-5p Suppression Aggravates Pyroptosis of Endothelial Cell in Deep Venous Thrombosis by Promoting Caspase-1

Front Cell Dev Biol. 2022 Apr 4:10:838785. doi: 10.3389/fcell.2022.838785. eCollection 2022.

Authors

Chu Chu¹, Bin Wang², Zhen Zhang³, Wen Liu³, Shangwen Sun⁴, Gang Liang², Xiaoshan Zhang², Hongqiang An², Ran Wei³, Xiaoxiao Zhu³, Qiang Guo³, Lin Zhao³, Xiaoxiao Fu³, Ke Xu³, Xia Li¹

Affiliations

¹ Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
² Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
³ School of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
⁴ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.

Abstract

Deep vein thrombosis (DVT) is a common peripheral vascular disease. Secondary pulmonary embolism (PE) caused by DVT leads to substantial patient death. Inflammation has been suggested as a key factor in the pathophysiology of DVT, however, involvement of pyroptosis-related inflammatory factors in DVT formation remains unclear. Here, we proposed that post-transcriptional modification of caspase-1 might be a crucial trigger for enhanced pyroptosis in vascular endothelial cells (VECs), and consequently contributed to severer symptoms in DVT patients. In order to explore the involvement of pyroptosis in DVT, peripheral blood mononuclear cells were collected from 30 DVT patients, and compared with the healthy controls, we found caspase-1 was increased both in mRNA and protein levels. miRNA microarray analysis demonstrated that down-regulated miR-513c-5p was significantly negatively correlated with the expression of caspase-1. In vitro assays suggested that miR-513c-5p overexpression could ameliorate the expression of caspase-1, and thus decreased the production of cleaved gasdermin D (GSDMD) and interleukin (IL)-1β and IL-18 in VECs. The dual-luciferase reporter assay identified direct binding between miR-513c-5p and the 3' untranslated region of caspase-1 encoding gene. The administration of miR-513c-5p mimics through tail vein injection or caspase-1 inhibitor (vx-765) by intraperitoneal injection remarkably decreased the volume of blood clots in vivo, whereas miR-513c-5p inhibitor aggravated thrombosis formation and this effect was dramatically weakened when treated in combination with vx-765. Collectively, these results revealed that the pyroptosis of VECs induced by decreased miR-513c-5p was involved in DVT progression and indicated a potential therapeutic strategy of targeting the miR-513c-5p/caspase-1/GSDMD signal axis for DVT management.

Keywords: caspase-1; deep venous thrombosis; miR-513c-5p; pyroptosis; vascular endothelial cell.