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β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Young Mice.

ABSTRACT: This study characterized β-aminopropionitrile (BAPN)-induced aortopathies in young mice. The effects of BAPN were first determined with regard to BAPN dose and mouse strain, age, and sex. BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the two aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice.

SUBMITTER: Franklin MK

PROVIDER: S-EPMC10602045 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

Franklin Michael K MK Sawada Hisashi H Ito Sohei S Howatt Deborah A DA Amioka Naofumi N Liang Ching-Ling CL Zhang Nancy N Graf David B DB Moorleghen Jessica J JJ Katsumata Yuriko Y Lu Hong S HS Daugherty Alan A

bioRxiv : the preprint server for biology 20240502

<h4>Background</h4>β-aminopropionitrile (BAPN) is a pharmacological inhibitor of lysyl oxidase and lysyl oxidase-like proteins. Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice.<h4>Methods</h4>BAPN was administered i ...[more]

PMID: 37886537

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Project description:Background Penetrating ulcers of aorta, aortic dissections and intramural hematomas all come under acute aortic syndromes and have important similarities and differences. Case report We report a 67?year old man with rupture of a large penetrating ulcer of the distal ascending aorta with hemopericardium and left hemothorax. He underwent interposition graft replacement of ascending aorta and hemi-arch with a 30?mm Gelweave Vascutek graft but represented 6?months later with development of a penetrating ulcer which ruptured into a huge 14?cm pseudoaneurysm. This was repaired with a 28?mm Vascutek Gelseal graft replacement of arch and interposition graft reconstruction of innominate and left common carotid arteries. 6?weeks later, however, he ruptured his proximal descending aorta and underwent TEVAR satisfactorily. Unfortunately, 2?days later, he developed a pathological fracture of left proximal tibia with metastasis from a primary renal cell carcinoma. He died 3?weeks later from respiratory failure. We shall briefly outline the similarities and differences in presentation and management of penetrating aortic ulcers, aortic dissections and intramural haematomas. We shall discuss, in greater detail, penetrating ulcers of thoracic aorta, their natural history, location, complications and management. Conclusion This case report is unique on account of initial successful surgical redressal following rupture of penetrating ulcer of distal ascending aorta into left pleural and pericardial cavities, normally associated with instant death. The haemodynamic effects of the rupture were staggered due to initial contained rupture into a smaller pseudoaneurysm, followed by a further rupture into a false aneurysmal sac followed eventually by generalised rupture into the pleural and pericardial cavities - a unique way of aortic rupture. Further development of another penetrating ulcer and a small pseudoaneurysm in the distal arch 6?months later which further ruptured into a larger 14?cm false aneurysmal sac, which again did not result in exsanguination, is again extraordinarily rare. Thereafter he underwent emergency thoracic endovascular aortic repair (TEVAR) for a further rupture of descending thoracic aorta. All three ruptures were managed successfully and would usually be associated with near-certain death, only for the patient to succumb eventually to the complications of metastatic renal cell carcinoma.

Project description:IntroductionIn patients with ascending aortic (AA) aneurysms, prosthetic graft replacement yields benefit but risk for complications in the descending aorta persists. Longitudinal impact of AA grafts on native descending aortic physiology is poorly understood.MethodsTransthoracic echocardiograms (echo) in patients undergoing AA elective surgical grafting were analyzed: Descending aortic deformation indices included global circumferential strain (GCS), time to peak (TTP) strain, and fractional area change (FAC). Computed tomography (CT) was used to assess aortic wall thickness and calcification.Results46 patients undergoing AA grafting were studied; 65% had congenital or genetically-associated AA (30% bicuspid valve, 22% Marfan, 13% other): After grafting (6.4±7.5 months), native descending aortic distension increased, irrespective of whether assessed based on circumferential strain or area-based methods (both p<0.001). Increased distensibility paralleled altered kinetics, as evidenced by decreased time to peak strain (p = 0.01) and increased velocity (p = 0.002). Augmented distensibility and flow velocity occurred despite similar pre- and post-graft blood pressure and medications (all p = NS), and was independent of pre-surgical aortic regurgitation or change in left ventricular stroke volume (both p = NS). Magnitude of change in GCS and FAC was 5-10 fold greater among patients with congenital or genetically associated AA vs. degenerative AA (p<0.001), paralleling larger descending aortic size, greater wall thickness, and higher prevalence of calcific atherosclerotic plaque in the degenerative group (all p<0.05). In multivariate analysis, congenital/genetically associated AA etiology conferred a 4-fold increment in magnitude of augmented native descending aortic strain after proximal grafting (B = 4.19 [CI 1.6, 6.8]; p = 0.002) independent of age and descending aortic size.ConclusionsProsthetic graft replacement of the ascending aorta increases magnitude and rapidity of distal aortic distension. Graft effects are greatest with congenital or genetically associated AA, providing a potential mechanism for increased energy transmission to the native descending aorta and adverse post-surgical aortic remodeling.

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β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Young Mice.

Publications

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

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