Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice

Okuyama, Michihiro; Jiang, Weihua; Javidan, Aida; Chen, Jeff Zheying; Howatt, Deborah A.; Yang, Lihua; Hamaguchi, Mika; Yasugi, Takumi; Aono, Jun; Vázquez-Padrón, Roberto I.; Subramanian, Venkateswaran

doi:10.1161/circulationaha.119.044986

Cited by 13 publications

(12 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since these AAA formed by elastase administration which causes severe elastin degradation in all mice, we had hypothesized that both male and female mice would form similar large aneurysms. Both sexes did form large aneurysms; however, the female mice had significantly larger aneurysms with higher inflammatory infiltrate than those of the males at the same time point, suggesting that there may be hormone-specific effects on aneurysmal growth 50 . While this likely does not fully explain the size discrepancies noted, further investigation would be necessary to provide additional mechanistic insight.…”

Section: Discussionmentioning

confidence: 92%

Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Berman

Romary

Kerr

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. In this study, we explore our ability to influence aneurysm growth in a topical elastase plus β-Aminopropionitrile (BAPN) mouse model by varying elastase concentration and by altering the cross-linking capability of the tissue. To do so, we assess both chronic and acute effects of elastase concentration using volumetric ultrasound. Our results suggest that the applied elastase concentration affects initial elastin degradation, as well as long-term vessel expansion. Additionally, we assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Removing BAPN reduces the aneurysm growth rate to near zero, resulting in a stable aneurysm. In contrast, adding BAPN causes a stable aneurysm to expand. Altogether, these results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. The findings open several new areas of investigation in a murine model that mimics many aspects of human AAA.

show abstract

Section: Discussionmentioning

confidence: 92%

Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Berman

Romary

Kerr

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…BAPN-induced TAA mouse models induce fragmentation of elastic fibers and loss of smooth muscle cells (SMCs) through inhibition of LOX activity in the aortic wall ( 27 , 28 ). Previous studies have reported that male mice have an increased susceptibility to AA formation compared with female mice through testosterone-mediated suppression of LOX activity ( 29 ). To increase the success rate of TAA in the mouse models, we selected male mice for model construction.…”

Section: Discussionmentioning

confidence: 99%

Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm

Xiang¹,

Abudupataer²,

Liu³

et al. 2023

JCI Insight

View full text Add to dashboard Cite

Ciprofloxacin use may be associated with adverse aortic events. However, the mechanism underlying the effect of ciprofloxacin on the progression of thoracic aortic aneurysm (TAA) is not well understood. Using an in vitro microphysiological model, we treated human aortic smooth muscle cells (HASMCs) derived from patients with bicuspid aortic valve (BAV)-or tricuspid aortic valve (TAV)-associated TAAs with ciprofloxacin. TAA C57/BL6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time polymerase chain reaction, western blotting, and RNA sequencing showed that ciprofloxacin exposure was associated with a downregulated contractile phenotype, an upregulated inflammatory reaction, and extracellular matrix (ECM) degradation in the normal HASMCs derived from the non-diseased aorta. Ciprofloxacin induced mitochondrial dysfunction in the HASMCs and further increased apoptosis by activating the ERK1/2 and P38 mitogen-activated protein kinase pathways. These adverse effects appeared to be more severe in the HASMCs derived from BAV-and TAV-associated TAAs than in the normal HASMCs when the ciprofloxacin concentration exceeded 100 µg/mL. In the aortic walls of the TAA-induced mice, ECM degradation and apoptosis were aggravated after ciprofloxacin exposure. Therefore, ciprofloxacin should be used with caution in patients with BAV-or TAV-associated TAAs.

show abstract

“…Although it has been reported that estrogen increases LOX in diverse connective tissues, including bones, skin, and the uterus 47,48 , a recent study using angiotensin II infusion in adult male Apoe -/- mice suggested that the stronger aortopathy in males was due to the androgens 49 . Importantly, orchiectomy and ovariectomy studies in WT mice suggest that androgens reduce LOX in the male aortas, hence rendering them vulnerable mechanically 50 . Conversely, an elastase + BAPN model of abdominal aortic aneurysms reported greater dilatation in female than male mice, though with low numbers of female mice 51 .…”

Section: Discussionmentioning

confidence: 99%

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Weiss

Rego

Cavinato

et al. 2022

Preprint

View full text Add to dashboard Cite

Transmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase (β-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.

show abstract

Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice

Cited by 13 publications

References 5 publications

Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Contact Info

Product

Resources

About