{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2024,3,3]],"date-time":"2024-03-03T13:07:46Z","timestamp":1709471266702},"posted":{"date-parts":[[2023,2,3]]},"group-title":"In Review","reference-count":27,"publisher":"Research Square Platform LLC","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n        <jats:p><jats:bold>Background: <\/jats:bold>Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with <jats:italic>PCSK9<\/jats:italic> LOF. In addition to direct influence on serum lipoprotein levels, PCSK9 likely exerts pleiotropic effects on vascular endothelium. Both mechanisms may influence sepsis outcomes. We sought to test the influence of <jats:italic>PCSK9<\/jats:italic> LOF genotype on endothelial dysfunction in pediatric sepsis.\n<jats:bold>Methods: <\/jats:bold>Secondary analyses of a prospective observational cohort of pediatric septic shock. Single nucleotide polymorphisms of <jats:italic>PCSK9<\/jats:italic> and <jats:italic>LDLR<\/jats:italic> genes were assessed. Serum PCSK9, lipoprotein, and endothelial marker concentrations were measured. Multivariable linear regression tested the influence of <jats:italic>PCSK9<\/jats:italic> LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses assessed impact of select endothelial markers on the association between <jats:italic>PCSK9 <\/jats:italic>LOF genotype and mortality. Juvenile <jats:italic>Pcsk9<\/jats:italic> null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified.\n<jats:bold>Results: <\/jats:bold>474 patients were included. <jats:italic>PCSK9<\/jats:italic> LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of patients homozygous for the rs688 <jats:italic>LDLR<\/jats:italic> variant that renders it insensitive to PCSK9. Serum PCSK9 levels did not correlate with endothelial dysfunction. <jats:italic>PCSK9<\/jats:italic>LOF significantly influenced concentrations of Angiopoietin-1 (Angpt-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). However, upon adjusting for LDL and HDL, <jats:italic>PCSK9<\/jats:italic>LOF remained significantly associated with low Angpt-1 alone. Causal Mediation Analysis demonstrated that the effect of <jats:italic>PCSK9<\/jats:italic> LOF on mortality was partially 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.\n<jats:bold>Conclusions: <\/jats:bold><jats:italic>PCSK9<\/jats:italic> LOF independently influences serum Angpt-1 levels in pediatric septic shock. Angpt-1 likely contributes mechanistically to the effect of <jats:italic>PCSK9<\/jats:italic> LOF on mortality in juvenile hosts. Mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of novel pediatric-specific sepsis therapies.<\/jats:p>","DOI":"10.21203\/rs.3.rs-2521836\/v1","type":"posted-content","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:06:20Z","timestamp":1675382780000},"source":"Crossref","is-referenced-by-count":0,"title":["Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1"],"prefix":"10.21203","author":[{"given":"Mihir R.","family":"Atreya","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie Z.","family":"Cvijanovich","sequence":"additional","affiliation":[{"name":"UCSF Benioff Children\u2019s Hospital Oakland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie C.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott L.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"Bigham","sequence":"additional","affiliation":[{"name":"Akron Children\u2019s Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parag N.","family":"Jain","sequence":"additional","affiliation":[{"name":"Texas Children\u2019s Hospital, Baylor College of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Orange County"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riad","family":"Lutfi","sequence":"additional","affiliation":[{"name":"Riley Hospital for Children"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Nowak","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital and Clinics of Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey L.","family":"Allen","sequence":"additional","affiliation":[{"name":"Children\u2019s Mercy Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal J.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Penn State Hershey Children\u2019s Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jocelyn R.","family":"Grunwell","sequence":"additional","affiliation":[{"name":"Children\u2019s Healthcare of Atlanta at Egleston"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Torrey","family":"Baines","sequence":"additional","affiliation":[{"name":"University of Florida Health Shands Children\u2019s Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Quasney","sequence":"additional","affiliation":[{"name":"CS Mott Children\u2019s Hospital at the University of Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bereketeab","family":"Haileselassie","sequence":"additional","affiliation":[{"name":"Lucile Packard Children\u2019s Hospital Stanford"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew N.","family":"Alder","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Lahni","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scarlett","family":"Ripberger","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical 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