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Circulating microparticles induced neutrophils chemotaxis through FOXO3a and the inhibiting role of dexmedetomidine in cardiorenal syndromes
Author(s) -
Ou Jing-song,
Yuan Hao-Xiang,
Chen Cai -Yun,
Li Yu-Quan,
Li Yan,
Xu Kang-Qing,
Ou Zhijun
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01936
Subject(s) - chemotaxis , microbiology and biotechnology , chemokine , phosphorylation , pharmacology , chemistry , biology , immunology , inflammation , receptor , biochemistry
Rationale Cardiorenal injury, also called cardiorenal syndromes, are the common complications in cardiac surgery. We previous demonstrated that circulating microparticles from patients with valvular heart disease (vMPs) and cardiac surgery contained inflammatory components and inhibited endothelium‐dependent vasodilation. However, the effects of vMPs on cardiorenal syndromes are unclear. Neutrophils chemotaxis plays an important role in cardiorenal syndromes. In addition, dexmedetomidine (DEX) could reduce cardiorenal syndromes in cardiac surgery. However, the effect of DEX on vMPs and neutrophils chemotaxis was unknown. Objective To investigate the effects and mechanisms of vMPs on heart and kidneys and the effect of DEX on vMPs and neutrophils chemotaxis. Methods and Results Circulating MPs were isolated from health subjects (nMPs) and patients with VHD. vMPs stimulated the C‐X‐C motif chemokine 4(CXCL4) and C‐C motif chemokine 5(CCL5) released from cultured human umbilical vein endothelial cells (HUVECs) and induced neutrophils chemotaxis. Silencing CXCL4 or CCL5 inhibited vMPs‐induced neutrophils chemotaxis. vMPs increased the expression of forkhead box proteins 3a (FOXO3a) and decreased the phosphorylation of AKT and FOXO3a, resulting in the transport of the FOXO3a from cytoplasm to nucleus and the activation of FOXO3a signaling pathway. Silencing FOXO3a reduced the vMPs‐induced CXCL4 and CCL5 as well as neutrophils chemotaxis. vMPs enhanced the levels of CXCL4 and CCL5 in plasma, the neutrophils accumulation, but inhibited the phosphorylation of AKT and FOXO3a and increased FOXO3a, leading to the activation of FOXO3a signaling pathway in the heart and kidneys, which could be inhibited by pretreated with DEX in vivo . Pretreated with DEX also reduced vMPs‐induced CXCL4 and CCL5 and neutrophils chemotaxis in cultured HUVECs. Conclusion vMPs induced CXCL4‐CCL5 to stimulate neutrophils infiltration in the heart and kidneys, which could be inhibited by DEX via FOXO3a signaling pathway. Our findings present a novel mechanism by which vMPs induce cardiorenal injury and may provided a new basis for the application of DEX in reducing cardiorenal syndromes in cardiac surgery. Support or Funding Information This research was financially supported by the National Natural Science Foundation of China (Grants 81670392, 81600382, 81770241, 81830013, 81970363 and Distinguished Young Scholar Grant 81325001), International Cooperation project (2015DFA31070) from the Ministry of Science and Technology of China, Guangdong Natural Science Fund Committee (Grant 2015A030312009), the Changjiang Scholars Program from the Ministry of Education of China, the Sun Yat‐sen University Clinical Research 5010 Program, Program of National Key Clinical Specialties.