Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.
Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.
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DOI：
10.1186/s13054-023-04535-1
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发表时间：
2023-06-26
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影响因子：
--
通讯作者：
Standage SW
中科院分区：
文献类型：
--
作者：
Atreya MR;Cvijanovich NZ;Fitzgerald JC;Weiss SL;Bigham MT;Jain PN;Schwarz AJ;Lutfi R;Nowak J;Allen GL;Thomas NJ;Grunwell JR;Baines T;Quasney M;Haileselassie B;Alder MN;Lahni P;Ripberger S;Ekunwe A;Campbell KR;Walley KR;Standage SW
败血症与显著的死亡率有关。然而，除了抗生素，没有其他有效的治疗方法。PCSK9功能丧失(LOF)和抑制，通过增强低密度脂蛋白受体(LDLR)介导的内毒素清除，有望成为一种潜在的成人治疗方法。相比之下，我们之前已经证明幼年宿主的死亡率更高。考虑到PCSK9对内皮的潜在多效性，除了对血清脂蛋白的典型影响外，这两种效应都可能影响脓毒症的结局，我们试图测试PCSK9 LOF基因对内皮功能障碍的影响。儿童感染性休克前瞻性观察队列的二次分析。先前已经确定了PCSK9和LDLR基因的遗传变异、血清PCSK9和脂蛋白浓度。检测第1天血清内皮细胞功能障碍标志物。我们进行了多变量线性回归，以检验PCSK9 LOF基因对血管内皮细胞标志物的影响，调整了年龄、复杂病程以及低密度脂蛋白和高密度脂蛋白。因果中介分析，以测试选定的内皮标记物对PCSK9 LOF基因和死亡率之间的关联的影响。对PCSK9基因缺失和野生型幼鼠造成盲肠浆液脓毒症，并对血管内皮细胞标志物进行定量。共纳入474名患者。PCSK9 LOF与几个内皮功能障碍的标记物相关，排除那些rs688 LDLR变异体的纯合后相关性增强，使其对PCSK9不敏感。血清PCSK9与内皮功能障碍无相关性。在调整了包括脂蛋白浓度在内的潜在混杂因素后，PCSK9LOF影响了血管生成素-1(Angpt-1)的浓度，假发现调整了包括低密度脂蛋白和高密度脂蛋白的模型的p值分别为0.042和0.013。因果中介分析表明，PCSK9 LOF对死亡率的影响是由Angpt-1介导的(p = 0.0008)。小鼠的数据证实了这些结果，与野生型相比，与野生型相比，在感染败血症的基因敲除小鼠中，Angpt-1较低，而可溶性血栓调节蛋白较高。我们提供的遗传和生物标记物关联数据表明，在感染性休克的发育中的宿主中，Angpt-1上的PCSK9-LDLR通路可能起着直接作用，并需要进行外部验证。此外，对PCSK9-LDLR通路在血管内稳态中作用的机制研究可能会导致儿科特异性脓毒症治疗的发展。网上版载有补充材料，可在10.1186/s13054-023-04535-1查阅。
Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction. Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies. The online version contains supplementary material available at 10.1186/s13054-023-04535-1.
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