The role of PCSK9 on monocyte recruitment, cytokine synthesis and extramedullary hematopoiesis in acute myocardial infarction.

PCSK9 对急性心肌梗死中单核细胞募集、细胞因子合成和髓外造血的作用。

• 批准号: 399790507
• 负责人: Dr. Jana Grune
• 金额: --
• 依托单位: Center for Systems Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399790507?language=en
• 关键词: role; PCSK9; monocyte; recruitment; cytokine

Elevated levels of Proprotein convertase subtilin-kexin 9 (PCSK9) induce deleterious cardiovascular effects, like an increase of circulating low-density lipoportein-cholesterol (LDL-C). Moreover, PCSK9 serum concentrations were shown to be upregulated directly after acute myocardial infarction (MI), indicating a role for PCSK9 during the acute period of ischemic myocardial injury. My own in vitro data revealed that PCSK9 regulates the chemotactic relevant peptide CCR2 (C-C motif chemokine receptor 2) on monocytes in a LDL-C/LDL-receptor (LDL-R) dependent manner. Newly made monocytes rely on CCR2 for their departure from the bone marrow and recruitment to the infarct. Previously, the Nahrendorf lab reported that shortly after MI hematopoietic stem and progenitor cells (HSPCs) are released from the bone marrow niche into the circulation in a CCR2 dependent manner, subsequently seeding the spleen and yielding a sustained boost in monocyte production. These data suggest a potential role for PCSK9 during acute MI, by regulating the chemokine receptor CCR2. I hypothesize that modulation of PCSK9 (in transgenic mouse models) contributes to the cardiac outcome and infarct healing after acute MI. I further hypothesize that elevated PCSK9 levels during MI lead to increased levels of plasma LDL-C and subsequent upregulation of CCR2. This will most likely stimulate splenic hematopoiesis and monocyte recruitment to the infarct, since CCR2 is necessary for monocyte infiltration. Vice versa, PCSK9 paucity should prevent cardiac monocyte recruitment, as the cells rely on the chemokine receptor for migration. Testing this hypothesis is of great clinical relevance, because anti-PCSK9 therapy has recently been granted FDA approval for patients with hypercholesterolemia. Arising evidence suggests that PCSK9 inhibitors reduce the prevalence of cardiovascular events like acute MI, pointing towards considerable adverse effects of PCSK9. However, some patients may develop acute MI despite anti-PCSK9 therapy. Therefore, further understanding of PCSK9’s molecular action on monocyte recruitment, cytokine synthesis and extramedullary hematopoiesis in acute MI is urgently needed.

前蛋白转化酶subtilin-kexin 9（PCSK 9）水平升高可诱导有害的心血管效应，如循环低密度脂蛋白胆固醇（LDL-C）增加。此外，PCSK 9血清浓度显示在急性心肌梗死（MI）后直接上调，表明PCSK 9在缺血性心肌损伤急性期的作用。我自己的体外数据显示，PCSK 9以LDL-C/LDL-受体（LDL-R）依赖性方式调节单核细胞上的趋化相关肽CCR 2（C-C基序趋化因子受体2）。新产生的单核细胞依赖于CCR 2使其离开骨髓并募集到梗死区。此前，Nazodorf实验室报道，MI后不久，造血干细胞和祖细胞（HSPC）以CCR 2依赖性方式从骨髓龛释放到循环中，随后接种脾脏并产生单核细胞产生的持续增强。这些数据表明PCSK 9在急性MI期间通过调节趋化因子受体CCR 2发挥潜在作用。我假设PCSK 9的调节（在转基因小鼠模型中）有助于急性MI后的心脏结局和梗死愈合。我进一步假设MI期间PCSK 9水平升高导致血浆LDL-C水平升高，随后CCR 2上调。这将最有可能刺激脾造血和单核细胞募集到梗死，因为CCR 2是单核细胞浸润所必需的。反之亦然，PCSK 9缺乏应该阻止心脏单核细胞募集，因为细胞依赖于趋化因子受体进行迁移。检验这一假设具有很大的临床意义，因为抗PCSK 9疗法最近已被FDA批准用于高胆固醇血症患者。越来越多的证据表明，PCSK 9抑制剂可降低心血管事件（如急性MI）的患病率，这表明PCSK 9具有相当大的不良反应。然而，尽管抗PCSK 9治疗，一些患者仍可能发生急性MI。因此，迫切需要进一步了解PCSK 9在急性MI中对单核细胞募集、细胞因子合成和髓外造血的分子作用。