Inhibition of FPR2 impaired leukocytes recruitment and elicited non resolving inflammation in acute heart failure
Inhibition of FPR2 impaired leukocytes recruitment and elicited non resolving inflammation in acute heart failure
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DOI：
10.1016/j.phrs.2019.104295
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发表时间：
2019-08-01
影响因子：
9.3
通讯作者：
Halade, Ganesh V.
中科院分区：
文献类型：
--
作者：
Kain, Vasundhara;Jadapalli, Jeevan Kumar;Halade, Ganesh V.
生活方式或年龄相关的危险因素过度激活炎症，从而触发心肌梗死(MI)后与急性心力衰竭(HF)相关的死亡。心肌梗死后激活的白细胞表达甲酰肽受体2(FPR2)，这是炎症消退和心脏愈合所必需的。然而，FPR2在急性心衰中的作用是不完整的，仍然令人感兴趣。在这里，我们的目的是确定药物抑制FPR2是否扰乱急性心力衰竭中白细胞的运输。雄性C57BL/6(8-12周)小鼠采用永久性冠状动脉结扎术进行急性心力衰竭(MI-D1)，造成不可逆的急性和慢性心衰。心肌梗死后3h皮下注射FPR2拮抗剂WRW4(1ug/kg/d)，维持生理盐水对照组。用流式细胞仪对白细胞进行定量，用超声心动图和组织学检查确认急性失代偿性心衰。抑制FPR2可降低左、脾组织中FPR2的表达。与心肌梗死对照组相比，给予WRW4抑制剂诱导未成熟和失活的中性粒细胞浸润Ly6G(Int)，并增强心肌梗死后左室壁Cc12的表达。白细胞分析显示，与心肌梗死对照组(49.1+/-2%)相比，注射WRW4的小鼠的单核细胞总数(23.3+/-2%)总体上减少了。抑制FPR2使F4/80(+)/Ly6C(Hi)促炎症巨噬细胞(14.8+/-2%)较心肌梗死对照组(10+/-1%)增加，并使促炎标记物TNF-α和IL-1β的转录增加，而与心肌梗死对照组相比，左心室Arg-1表达降低提示急性炎症反应受损。使用WRW4抑制FPR2还通过启动未成熟的中性粒细胞而扰乱脾心白细胞的募集，从而导致急性失代偿性心力衰竭心肌梗死后不完全分解信号的开始。
Lifestyle or age-related risk factors over-activate the inflammation that triggers acute heart failure (HF)-related mortality following myocardial infarction (MI). Post-MI activated leukocytes express formyl peptide receptor 2 (FPR2) that is essential for inflammation-resolution and in cardiac healing. However, the role of FPR2 in acute HF is incomplete and remain of interest. Here, we aimed to determine whether pharmacological inhibition of FPR2 perturb leukocyte trafficking in acute HF. Male C57BL/6 (8-12 weeks) mice were subjected to acute HF (MI-d1) using permanent coronary artery ligation that develops irreversible acute and chronic heart failure. FPR2 antagonist WRW4 (1 mu g/kg/day) was subcutaneously injected 3 h post-MI maintaining saline-injected MI-controls. Leukocytes were quantitated using flow cytometry, and acute decompensated HF was confirmed using echocardiography and histology. FPR2 inhibition decreased the expression of FPR2 in the LV and spleen tissues. Administration of WRW4 inhibitor to mice primed immature and inactive neutrophils infiltration Ly6G(int) and intensified the Cc12 expression compared to MI-control in the infarcted LV post-MI. Leukocyte profiling revealed an overall decrease in monocytes (23.3 +/- 2%) in WRW4-injected mice compared with MI-control (49.1 +/- 2%) in infarcted LV. FPR2 inhibition increased F4/80(+)/Ly6C(hi) pro-inflammatory macrophages (14.8 +/- 2%) compared with MI-control (10 +/- 1%) with increased transcripts of pro-inflammatory markers TNF-alpha and IL-1 beta, and decreased Arg-1 expression in the infarcted LV compared to MI-controls is suggestive of the impaired acute inflammatory response. Inhibition of FPR2 using WRW4 also disturbed splenocardiac leukocytes recruitment by priming immature neutrophils leading to the onset of incomplete resolution signaling in acute decompensated HF post-MI.