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Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression.
Griepke, Silke; Grupe, Emilie; Lindholt, Jes Sanddal; Fuglsang, Elizabeth Hvitfeldt; Steffensen, Lasse Bach; Beck, Hans Christian; Larsen, Mia Dupont; Bang-Møller, Sissel Karoline; Overgaard, Martin; Rasmussen, Lars Melholt; Lambertsen, Kate Lykke; Stubbe, Jane.
Afiliação
  • Griepke S; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Grupe E; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Lindholt JS; Elite Research Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
  • Fuglsang EH; Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark.
  • Steffensen LB; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Beck HC; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Larsen MD; Elite Research Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
  • Bang-Møller SK; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
  • Overgaard M; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Rasmussen LM; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • Lambertsen KL; Elite Research Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
  • Stubbe J; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Front Cardiovasc Med ; 9: 942342, 2022.
Article em En | MEDLINE | ID: mdl-36186984
Background: Tumor necrosis factor (TNF) is pathologically elevated in human abdominal aortic aneurysms (AAA). Non-selective TNF inhibition-based therapeutics are approved for human use but have been linked to several side effects. Compounds that target the proinflammatory soluble form of TNF (solTNF) but preserve the immunomodulatory capabilities of the transmembrane form of TNF (tmTNF) may prevent these side effects. We hypothesize that inhibition of solTNF signaling prevents AAA expansion. Methods: The effect of the selective solTNF inhibitor, XPro1595, and the non-selective TNF inhibitor, Etanercept (ETN) was examined in porcine pancreatic elastase (PPE) induced AAA mice, and findings with XPro1595 was confirmed in angiotensin II (ANGII) induced AAA in hyperlipidemic apolipoprotein E (Apoe) -/- mice. Results: XPro1595 treatment significantly reduced AAA expansion in both models, and a similar trend (p = 0.06) was observed in PPE-induced AAA in ETN-treated mice. In the PPE aneurysm wall, XPro1595 improved elastin integrity scores. In aneurysms, mean TNFR1 levels reduced non-significantly (p = 0.07) by 50% after TNF inhibition, but the histological location in murine AAAs was unaffected and similar to that in human AAAs. Semi-quantification of infiltrating leucocytes, macrophages, T-cells, and neutrophils in the aneurysm wall were unaffected by TNF inhibition. XPro1595 increased systemic TNF levels, while ETN increased systemic IL-10 levels. In ANGII-induced AAA mice, XPro1595 increased systemic TNF and IL-5 levels. In early AAA development, proteomic analyses revealed that XPro1595 significantly upregulated ontology terms including "platelet aggregation" and "coagulation" related to the fibrinogen complex, from which several proteins were among the top regulated proteins. Downregulated ontology terms were associated with metabolic processes. Conclusion: In conclusion, selective inhibition of solTNF signaling reduced aneurysm expansion in mice, supporting its potential as an attractive treatment option for AAA patients.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article