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Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression

ABSTRACT: Tumor necrosis factor (TNF) is elevated in human abdominal aortic aneurysms (AAA). Non-selective TNF inhibition has been linked to several severe side effects. Compounds that target the proinflammatory soluble TNF (solTNF) while preserving the immunomodulatory capabilities of transmembrane TNF (tmTNF) may prevent such side effects. We hypothesize that inhibition of solTNF signaling by XPro1595 is just as effective as non-selective TNF inhibition by etanercept (ETN) in preventing AAA expansion. The effect of XPro1595 and ETN was examined in porcine pancreatic elastase (PPE) induced AAA mice and findings of XPro1595 was confirmed in Angiotensin II (AngII) induced AAA in hyperlipidemic apolipoprotein E (Apoe) -/- mice. XPro1595 treatment significantly reduced AAA expansion in both models, while a similar trend (p=0.06) was observed in ETN-treated mice using the PPE model. In the PPE aneurysm wall, elastin integrity scores were significantly improved in the XPro1595 group. In the aneurysms, mean TNFR1wasreduced no-significantly (p=0.07) by 50% non-significant after TNF inhibition, but the cellular location in murine AAAs were unaffected and like the localization in human AAAs. Systemic TNF levels were elevated in XPro1595-treated mice, while systemic IL-10 levels were significantly increased after ETN-treatment, while in AngII induced AAA mice systemic TNF and IL5 levels were elevated after XPro1595 treatment. In early AAA development, proteomic analyses revealed that components of the fibrinogen complex were elevated while prostaglandin E2 synthase was down regulated by Xpro1595 (unadjusted p-values). David’s ontology analyses revealed that several pathways including cell matrix adhesion, extracellular space, fibrinogen complex, blood microparticles and glycoproteins were elevated by XPro1595 treatment. In conclusion, selective inhibition of solTNF reduces aneurysm expansion. This supports targeting solTNF as an attractive treatment option for AAA patients.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Abdominal Aorta

DISEASE(S): Abdominal Aorta Artery

SUBMITTER: Hans Christian Beck

LAB HEAD: Hans Christian Beck

PROVIDER: PXD035178 | Pride | 2022-10-14

REPOSITORIES: Pride

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Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression.

Griepke Silke S Grupe Emilie E Lindholt Jes Sanddal JS Fuglsang Elizabeth Hvitfeldt EH Steffensen Lasse Bach LB Beck Hans Christian HC Larsen Mia Dupont MD Bang-Møller Sissel Karoline SK Overgaard Martin M Rasmussen Lars Melholt LM Lambertsen Kate Lykke KL Stubbe Jane J

Frontiers in cardiovascular medicine 20220916

<h4>Background</h4>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 expansi ...[more]

PMID: 36186984

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Project description:Background: Abdominal Aortic Aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. Activating transcription factor (ATF) 3 has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive. Methods: Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell (VSMC)-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 (rAAV9) vectors carrying ATF3, or shRNA-ATF3 with SM22α promoter were used in AngII (angiotensin II) induced AAA mice. In human and murine VSMCs, gain or loss of function experiments were performed to investigate the role of ATF3 in VSMC proliferation and apoptosis. Results: In both AngII-induced AAA mice and AAA patients, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in VSMC promoted AAA formation in AngII-induced AAA mice. PDGFRB was identified as the target of ATF3, which mediated VSMC proliferation in response to TNF-alpha at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our ChIP results also demonstrated that the recruitment of NFκB1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (Andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development. Conclusions: Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

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