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GW24-e1138 The Mitochondrial DAMP fMLP activates Nlrp3 Inflammasome which Promotes Angiogenesis after Hindlimb Ischemia
  1. Liu Huanbo1,2,
  2. Liang Chun1,
  3. Chen AF2,
  4. Wu Zonggui1
  1. 1Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
  2. 2Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Abstract

Objectives Peripheral arterial disease (PAD) is a systemic inflammatory disorder that affect millions of people worldwide. The secretion of Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) is controlled by inflammasomes. Rencent study showed that Nlrp3 inflammasome activation was linked to mitochondrial dysfunction and damaged tissue could release mitochondrial DAMPs. The role of Nlrp3 inflammasome in PAD is still unknown. The present study investigated the role of Nlrp3 inflammasome in mouse hindlimb ischaemia and whether mitochondrial DAMP fMLP could activate Nlrp3 inflammasome.

Methods Hindlimb ischaemia was induced in C56BL/6, Nlrp3 knockout and Caspase 1 knockout mice. Blood flow recovery was measured by Laser Doppler Perfusion Imaging (LDPI) each week. The mobilisation and function of endothelial progenitor cells (EPCs) of these mice were tested. Bone marrow derived macrophage cells (BMMCs) of these mice were treated with fMLP and hypoxia. IL-1β and IL-18 were examined in plasma and supernatant of cell culture medium after treatment.

Results The blood flow recovery of Nlrp3 knockout mice and Caspase 1 knockout mice was retarded compared with wild type mice. Nlrp3 and Caspase1 deficiency dampened mobilisation and adhesion but not tube formation or migration capability of EPCs. Mitochondrial DAMP fMLP together with hypoxia activated Nlrp3 inflammasome in BMMCs and induced the release of IL-1β, which was Caspase 1 dependent. IL-1β and IL-18 subsequently promoted tube formation capability of EPCs.

Conclusions The Mitochondrial DAMP fMLP activated the Nlrp3 Inflammasome, which promoted angiogenesis after hindlimb Ischaemia.

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