Translating mouse models of abdominal aortic aneurysm to the translational needs of vascular surgery

Busch, Albert; Bleichert, Sonja; Ibrahim, Nahla Khamis; Wortmann, Markus; Eckstein, Hans‐Henning; Brostjan, Christine; Wagenhäuser, Markus U.; Goergen, Craig J.; Maegdefessel, Lars

doi:10.1016/j.jvssci.2021.01.002

Cited by 27 publications

(41 citation statements)

References 139 publications

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“…Elastase Induced AAA Have More Inflammatory and Immune Pathways Than That of Ang-II Induced AAA Ang-II induced, elastase induced, and calcium chloride/phosphate induced AAA are three commonly used mouse models (86) in addition to a few surgical mouse models (87) for the induction of AAA. We then hypothesized that elastase induced AAA aortas differentially modulate the expression of secretomic genes from that of Ang-II AAA aortas.…”

Section: Atherosclerotic Aortas Upregulate T Cell and B Cell Adaptive...mentioning

confidence: 99%

Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

Sun

et al. 2022

Front. Immunol.

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To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel–Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang-II induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase 1 SGs play roles at early MERS-CoV infected ECs whereas caspase 4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase 1 SGs may function as drivers for trained immunity (innate immune memory); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.

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Section: Atherosclerotic Aortas Upregulate T Cell and B Cell Adaptive...mentioning

confidence: 99%

Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

Sun

et al. 2022

Front. Immunol.

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“…A nondissecting AAA will typically form in two weeks, making this a suitable model for prevention studies. Marked macrophage infiltration and increased MMP expression seen in the aorta closely parallels human pathology [ 72 , 76 ]. One disadvantage of the elastase model is that the size and severity of the AAAs that form varies greatly [ 77 ].…”

Section: Animal Models Of Aaamentioning

confidence: 99%

“…Elastase is a nondissecting model whereas AngII infusion is. A robust mouse model of AAA should reflect human characteristics such as fibrosis, thrombus, changes in hemodynamics, immune response, calcification, and rupture [ 76 ]. The field is still searching for a robust animal model of AAA that accurately captures the disease features seen in humans.…”

Section: Animal Models Of Aaamentioning

confidence: 99%

Development of pharmacotherapies for abdominal aortic aneurysms

Weaver¹,

Loftin²,

Zhan³

2022

Biomedicine & Pharmacotherapy

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“…Aneurysms in this model depict both features of AA and AD ( 20 ). Each of the different models, which have been developed for the research of aortic disease, has unique characteristics, and reflects different facets of human disease ( 40 ). In general, confirmation of the results from one model by use of another model seems rational but has not been performed for the four substances identified in this systematic review.…”

Section: Limitationsmentioning

confidence: 99%

Inflammasome Targeted Therapy as Novel Treatment Option for Aortic Aneurysms and Dissections: A Systematic Review of the Preclinical Evidence

Wortmann

Klotz

Kalkum

et al. 2022

Front. Cardiovasc. Med.

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Both aortic aneurysm and dissection are life threatening pathologies. In the lack of a conservative medical treatment, the only therapy consists of modifying cardiovascular risk factors and either surgical or endovascular treatment. Like many other cardiovascular diseases, in particular atherosclerosis, aortic aneurysm and dissection have a strong inflammatory phenotype. Inflammasomes are part of the innate immune system. Upon stimulation they form multi protein complexes resulting mainly in activation of interleukin-1β and other cytokines. Considering the gathering evidence, that inflammasomes are decisively involved in the emergence and progression of aortic diseases, inflammasome targeted therapy provides a promising new treatment approach. A systematic review following the PRISMA guidelines on the current preclinical data regarding the potential role of inflammasome targeted drug therapy as novel treatment option for aortic aneurysms and dissections was performed. Included were all rodent models of aortic disease (aortic aneurysm and dissection) evaluating a drug therapy with direct or indirect inhibition of inflammasomes and a suitable control group with the use of the same aortic model without the inflammasome targeted therapy. Primary and secondary outcomes were incidence of aortic disease, aortic rupture, aortic related death, and the maximum aortic diameter. The literature search of MEDLINE (via PubMed), the Web of Science, EMBASE and the Cochrane Central Registry of Registered Trials (CENTRAL) resulted in 8,137 hits. Of these, four studies met the inclusion criteria and were therefore eligible for data analysis. In all of them, targeting of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome effectively reduced the incidence of aortic disease and aortic rupture, and additionally reduced destruction of the aortic wall. Treatment strategies aiming at other inflammasomes could not be identified. In conclusion, inflammasome targeted therapies, more precisely targeting the NLRP3 inflammasome, have shown promising results in rodent models and deserve further investigation in preclinical research to potentially translate them into clinical research for the treatment of human patients with aortic disease. Regarding other inflammasomes, more preclinical research is needed to investigate their role in the pathophysiology of aortic disease.Protocol Registration: PROSPERO 2021 CRD42021279893, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021279893

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Translating mouse models of abdominal aortic aneurysm to the translational needs of vascular surgery

Cited by 27 publications

References 139 publications

Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation—Early Secretomes may Serve as Drivers for Trained Immunity

Development of pharmacotherapies for abdominal aortic aneurysms

Inflammasome Targeted Therapy as Novel Treatment Option for Aortic Aneurysms and Dissections: A Systematic Review of the Preclinical Evidence

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