Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1
© 2023. The Author(s)..
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
|---|---|
| Enthalten in: |
Critical care (London, England) - 27(2023), 1 vom: 26. Juni, Seite 250 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Atreya, Mihir R [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.07.2023 Date Revised 29.09.2023 published: Electronic UpdateOf: Res Sq. 2023 Feb 03;:. - PMID 36778250 Citation Status MEDLINE |
|---|
| doi: |
10.1186/s13054-023-04535-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM358670144 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM358670144 | ||
| 003 | DE-627 | ||
| 005 | 20231226075235.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s13054-023-04535-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1195.xml |
| 035 | |a (DE-627)NLM358670144 | ||
| 035 | |a (NLM)37365661 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Atreya, Mihir R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.07.2023 | ||
| 500 | |a Date Revised 29.09.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a UpdateOf: Res Sq. 2023 Feb 03;:. - PMID 36778250 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a RESULTS: 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 | ||
| 520 | |a CONCLUSIONS: 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 | ||
| 650 | 4 | |a Observational Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Biomarkers | |
| 650 | 4 | |a Endothelial dysfunction | |
| 650 | 4 | |a Endothelium | |
| 650 | 4 | |a Genotype | |
| 650 | 4 | |a LDLR | |
| 650 | 4 | |a Lipoproteins | |
| 650 | 4 | |a Multiple organ dysfunction syndrome | |
| 650 | 4 | |a PCSK9 | |
| 650 | 4 | |a Sepsis | |
| 650 | 4 | |a Septic shock | |
| 650 | 7 | |a Angiopoietin-1 |2 NLM | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Lipoproteins |2 NLM | |
| 650 | 7 | |a PCSK9 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Pcsk9 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Proprotein Convertase 9 |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 700 | 1 | |a Cvijanovich, Natalie Z |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzgerald, Julie C |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Scott L |e verfasserin |4 aut | |
| 700 | 1 | |a Bigham, Michael T |e verfasserin |4 aut | |
| 700 | 1 | |a Jain, Parag N |e verfasserin |4 aut | |
| 700 | 1 | |a Schwarz, Adam J |e verfasserin |4 aut | |
| 700 | 1 | |a Lutfi, Riad |e verfasserin |4 aut | |
| 700 | 1 | |a Nowak, Jeffrey |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Geoffrey L |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Neal J |e verfasserin |4 aut | |
| 700 | 1 | |a Grunwell, Jocelyn R |e verfasserin |4 aut | |
| 700 | 1 | |a Baines, Torrey |e verfasserin |4 aut | |
| 700 | 1 | |a Quasney, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Haileselassie, Bereketeab |e verfasserin |4 aut | |
| 700 | 1 | |a Alder, Matthew N |e verfasserin |4 aut | |
| 700 | 1 | |a Lahni, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Ripberger, Scarlett |e verfasserin |4 aut | |
| 700 | 1 | |a Ekunwe, Adesuwa |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Kyle R |e verfasserin |4 aut | |
| 700 | 1 | |a Walley, Keith R |e verfasserin |4 aut | |
| 700 | 1 | |a Standage, Stephen W |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Critical care (London, England) |d 1997 |g 27(2023), 1 vom: 26. Juni, Seite 250 |w (DE-627)NLM097399787 |x 1466-609X |7 nnns |
| 773 | 1 | 8 | |g volume:27 |g year:2023 |g number:1 |g day:26 |g month:06 |g pages:250 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s13054-023-04535-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 27 |j 2023 |e 1 |b 26 |c 06 |h 250 | ||