Berger Jean-Mathieu, Loza Valdes Angel, Gromada Jesper, Anderson Norma, Horton Jay D
Departments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX.
Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
J Lipid Res. 2017 Aug;58(8):1661-1669. doi: 10.1194/jlr.M076844. Epub 2017 Jun 9.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that targets LDL receptors (LDLRs) for degradation in liver. Blocking the interaction of PCSK9 with the LDLR potently reduces plasma LDL cholesterol levels and cardiovascular events. Recently, it has been suggested that inhibition of PCSK9 might also improve outcomes in mice and humans with sepsis, possibly by increasing LDLR-mediated clearance of endotoxins. Sepsis is a complication of a severe microbial infection that has shared pathways with lipid metabolism. Here, we tested whether anti-PCSK9 antibodies prevent death from lipopolysaccharide (LPS)-induced endotoxemia. Mice were administered PCSK9 antibodies prior to, or shortly after, injecting LPS. In both scenarios, the administration of PCSK9 antibodies did not alter endotoxemia-induced mortality. Afterward, we determined whether the complete absence of PCSK9 improved endotoxemia-induced mortality in mice with the germ-line deletion of Similarly, PCSK9 knockout mice were not protected from LPS-induced death. To determine whether low LDLR expression increased LPS-induced mortality, mice and PCSK9 transgenic mice were studied after injection of LPS. Endotoxemia-induced mortality was not altered in either mouse model. In a human cohort, we observed no correlation between plasma inflammation markers with total cholesterol levels, LDL cholesterol, and PCSK9. Combined, our data demonstrate that PCSK9 inhibition provides no protection from LPS-induced mortality in mice.
前蛋白转化酶枯草溶菌素/九型凯新蛋白酶（PCSK9）是一种分泌蛋白，可靶向肝脏中的低密度脂蛋白受体（LDLR）进行降解。阻断PCSK9与LDLR的相互作用可有效降低血浆低密度脂蛋白胆固醇水平和心血管事件。最近，有人提出抑制PCSK9可能还会改善脓毒症小鼠和人类的预后，可能是通过增加LDLR介导的内毒素清除来实现。脓毒症是严重微生物感染的一种并发症，与脂质代谢有共同途径。在此，我们测试了抗PCSK9抗体是否能预防脂多糖（LPS）诱导的内毒素血症导致的死亡。在注射LPS之前或之后不久给小鼠施用PCSK9抗体。在这两种情况下，施用PCSK9抗体均未改变内毒素血症诱导的死亡率。之后，我们确定完全缺乏PCSK9是否能改善种系缺失小鼠的内毒素血症诱导的死亡率。同样，PCSK9基因敲除小鼠也不能免受LPS诱导的死亡。为了确定低LDLR表达是否会增加LPS诱导的死亡率，在注射LPS后对 小鼠和PCSK9转基因小鼠进行了研究。在这两种小鼠模型中，内毒素血症诱导的死亡率均未改变。在一个人类队列中，我们观察到血浆炎症标志物与总胆固醇水平、低密度脂蛋白胆固醇和PCSK9之间无相关性。综合来看，我们的数据表明抑制PCSK9不能保护小鼠免受LPS诱导的死亡。
