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

原蛋白转换酶枯草杆菌毒素9(PCSK9)水平升高会导致有害的心血管效应，如循环低密度脂蛋白-胆固醇(LDL-C)的增加。此外，PCSK9的血清浓度在急性心肌梗死(MI)后立即升高，表明PCSK9在缺血性心肌损伤的急性期起作用。我自己的体外数据显示，PCSK9以低密度脂蛋白/低密度脂蛋白受体(LDL-R)依赖的方式调节单核细胞表面趋化相关肽CCR2(C-C基序趋化因子受体2)。新制造的单核细胞依赖CCR2从骨髓中分离并重新聚集到梗塞中。此前，纳伦多夫实验室报告说，心肌梗死后不久，造血干细胞和祖细胞(HSPC)以CCR2依赖的方式从骨髓利基释放到循环中，随后种植到脾中，并产生持续的单核细胞生成增加。这些数据表明，PCSK9可能通过调节趋化因子受体CCR2在急性心肌梗死期间发挥作用。我假设PCSK9的调节(在转基因小鼠模型中)有助于急性心肌梗死后的心脏结局和梗塞愈合。我进一步假设，心肌梗死期间PCSK9水平升高会导致血浆低密度脂蛋白-C水平升高，从而导致CCR2表达上调。这很可能会刺激脾造血和单核细胞重新聚集到梗死灶，因为CCR2是单核细胞渗透所必需的。反之亦然，PCSK9的缺乏应该会阻止心肌单核细胞的募集，因为细胞依赖趋化因子受体进行迁移。验证这一假设具有重要的临床意义，因为抗PCSK9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，PCSK9抑制剂可以降低急性心肌梗死等心血管事件的发生率，这表明PCSK9有相当大的不良影响。然而，尽管接受了抗PCSK9治疗，一些患者仍可能发生急性心肌梗死。因此，迫切需要进一步了解PCSK9的S分子在急性心肌梗死单核细胞募集、细胞因子合成和髓外造血中的作用。

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.