Upregulation of miR-223 abrogates NLRP3 inflammasome-mediated pyroptosis to attenuate oxidized low-density lipoprotein (
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Upregulation of miR-223 abrogates NLRP3 inflammasome-mediated pyroptosis to attenuate oxidized low-density lipoprotein (ox-LDL) -induced cell death in human vascular endothelial cells (ECs) Xumin Wang 1 & Xinwei Li 2 & Yuhong Wu 1 & Yuan Song 3 Received: 3 June 2020 / Accepted: 10 August 2020 / Editor: Tetsuji Okamoto # The Society for In Vitro Biology 2020
Abstract MiR-223 is closely associated with pathogenesis of coronary artery disease (CAD); however, the molecular mechanisms are unclear. In the present study, the human vascular endothelial cells (ECs) were isolated from patients undergoing coronary artery bypass graft and treated with oxidized low-density lipoprotein (ox-LDL) to induce cellular CAD models in vitro. We found that ox-LDL inhibited cell proliferation and viability, and promoted cell apoptosis in ECs. Of note, ox-LDL promoted cell pyroptosis, and both the pyroptosis inhibitor necrosulfonamide (NSA) and NLRP3 ablation restored cell viability in ECs treated with oxLDL, indicating that ox-LDL induced EC death by triggering cell pyroptosis. In addition, miR-223 was downregulated by oxLDL in ECs, and miR-223 overexpression rescued cell viability in ECs treated with ox-LDL. Interestingly, there existed targeting sites in miR-223 and 3′ untranslated regions (3′ UTRs) of NLRP3 mRNA, and further experiments validated that miR-223 negatively regulated NLRP3 expressions in ECs at both transcriptional and translational levels. Finally, we verified that upregulation of NLRP3 abrogated the protective effects of miR-223 overexpression on ox-LDL-treated ECs. Collectively, this in vitro study proved that overexpression of miR-223 protected ox-LDL-stimulated ECs from death through inactivating NLRP3 inflammasome-mediated pyroptotic cell death. Keywords Coronary artery disease . MiR-223 . NLRP3 . Cell pyroptosis . Oxidized low-density lipoprotein
Introduction Xumin Wang and Xinwei Li are co-first authors. * Yuan Song [email protected] Xumin Wang [email protected] Xinwei Li [email protected] Yuhong Wu [email protected] 1
Department of Cardiovascular Medicine, Affiliated Sixth Hospital of Xinjiang Medical University, Wuxing South Road 39, Urumqi 830000, Xinjiang, China
2
Department of Cardiovascular Medicine, Changji Branch, Affiliated First Hospital of Xinjiang Medical University, Qingnian South Road 73, Changji 831100, Xinjiang, China
3
Department of Function Examination, Affiliated Sixth Hospital of Xinjiang Medical University, Wuxing South Road 39, Urumqi 830000, Xinjiang, China
Coronary artery disease (CAD) is a common cardiovascular disease (CVD) (Raggi 2017; Musunuru and Kathiresan 2019), and the current therapies for CAD are mainly percutaneous coronary intervention and coronary artery bypass surgery (Kandaswamy and Zuo 2018). However, patients with CAD still had a worse prognosis with high mortality rate as the results of its complicated pathogenesis (Head et al. 2018). Recent data suggested that CAD is always accompanied by endothelial injury (Gao et al. 2020), which contributed to coronary a
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