β-Aminopropionitrile monofumarate induces thoracic aortic dissection in C57BL/6 mice

Abstract

Thoracic aortic dissection (TAD) is a catastrophic disease with high mortality and morbidity, characterized by fragmentation of elastin and loss of smooth muscle cells. However, the underlying pathological mechanisms of this disease remain elusive because there are no appropriate animal models, limiting discovery of effective therapeutic strategies. We treated mice on C57BL/6 and FVB genetic backgrounds with β-aminopropionitrile monofumarate (BAPN), an irreversible inhibitor of lysyl oxidase, for 4 wk, followed by angiotensin II (Ang II) infusion for 24 h. We found that the BAPN plus Ang II treatment induced formation of aortic dissections in 100% of mice on both genetic backgrounds. BAPN without Ang II caused dissections in few FVB mice, but caused 87% of C57BL/6 mice to develop TAD, with 37% dying from rupture of the aortic dissection. Moreover, a lower dose of BAPN induced TAD formation and rupture earlier with fewer effects on body weight. Therefore, we have generated a reliable and convenient TAD model in C57BL/6 mice for studying the pathological process and exploring therapeutic targets of TAD.

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

“…Degeneration and disorganisation of elastic lamina are characteristic histological changes observed in thoracic aortas of TAD patients. 9 Current models of TAD include BAPN administration, 10 AngII perfusion, 11 and genetic mutations. However, AngII administration is likely to trigger, rather than serve, as a pathological mediator of TAD and rupture.…”

“…However, AngII administration is likely to trigger, rather than serve, as a pathological mediator of TAD and rupture. 10 Moreover, knockout of collagen fibrillogenesis and ECM assembly related genes such as LOX 12 and Blotchy 13 has been associated with perinatal death and skeletal, muscular, and skin abnormalities in mice. LOX cross links elastin fibres and collagen fibres, and thus plays a critical role in maintaining homeostasis of the elastic lamina.…”

“…Despite the inability of BAPN to fully simulate clinical TAD (e.g., blood pressure does not rise in BAPN induced TAD models), it is still widely used as TAD model for pathophysiological studies. 10,14 HIFs are central mediators of cellular adaption to hypoxia. HIF-1a regulated LOX expression at the mRNA level.…”

ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection

“…The TAAD mice model was induced as described recently [3]. In brief, 3-week-old male mice were given a normal diet and administered a solution of BAPN (β-aminopropionitrile, Sigma–Aldrich, St. Louis, MO), which was dissolved in drinking water at a concentration of 1 g/kg per day for 4 weeks.…”

Aortic Aneurysms

“…125 In addition to AngII-induced TAA, co-infusion of AngII and β-aminopropionitrile also induces TAA in mice. 34,126 Ikonomidis and colleagues developed a mouse model of TAA by applying calcium chloride onto the descending thoracic aortic region. 127 Using these mouse models, recent studies discovered that genetic depletion of AT1 receptor reduced AngII-induced TAA; 128,129 nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) caspase-1 inflammasome contributed to AngII-induced TAA; 40 smooth muscle cell-specific deficiency of low-density lipoprotein receptor-related protein 1 augmented AngII-induced TAA; 130 genetic MMP-2 deficiency accelerated AngII-induced TAA, but attenuated calcium chloride-induced TAA; 123 and smooth muscle cell-specific deficiency of hypoxia-inducible factor-1α increased TAA in mice co-infused with AngII and β-aminopropionitrile.…”