Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response, and Increases Survival in A Murine Model of Endotoxic Shock.
Animals
Cytokines
/ metabolism
Disease Models, Animal
Lipopolysaccharides
/ toxicity
Male
Mice
Mice, Inbred C57BL
NF-kappa B
/ metabolism
Peptide Fragments
/ therapeutic use
Random Allocation
Receptors, G-Protein-Coupled
/ metabolism
Shock, Septic
Transcription Factor RelA
/ metabolism
Urotensins
/ therapeutic use
Journal
Shock (Augusta, Ga.)
ISSN: 1540-0514
Titre abrégé: Shock
Pays: United States
ID NLM: 9421564
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
pubmed:
1
10
2019
medline:
3
8
2021
entrez:
1
10
2019
Statut:
ppublish
Résumé
Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. Urantide treatment improved survival (88.9% vs. 30% on day 6, P < 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2,485 [2,280-2,751] pg/mL vs. 3,330 [3,119-3,680] pg/mL, P < 0.01) at H6, in IL-3 (1.0 [0.40-2.0] pg/mL vs. 5.8 [3.0-7.7] pg/mL, P < 0.01), and IL-1β (651 [491-1,135] pg/mL vs. 1,601 [906-3,010] pg/mL, P < 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9-1.9] vs. 3.2 [2.3-4], P < 0.01) and kidney (0.3 [0.3-0.4] vs. 0.6 [0.5-1.1], P < 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5-38.9] vs. 12.0 [8.7-17.6] %, P < 0.01 and cardiac output: 30.3 [25.9-39.8] vs. 15.1 [13.0-16.9] mL/min, P < 0.0001). These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction, and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients.
Identifiants
pubmed: 31568223
doi: 10.1097/SHK.0000000000001448
pii: 00024382-202010000-00018
doi:
Substances chimiques
Cytokines
0
Lipopolysaccharides
0
NF-kappa B
0
Peptide Fragments
0
Receptors, G-Protein-Coupled
0
Transcription Factor RelA
0
Urotensins
0
urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
574-582Références
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