A novel reproducible model of aortic aneurysm rupture

Fashandi, Anna Z.; Hawkins, Robert B.; Salmon, Morgan; Spinosa, Michael; Montgomery, William G.; Cullen, J. Michael; Lu, Guanyi; Su, Gang; Ailawadi, Gorav; Upchurch, Gilbert R.

doi:10.1016/j.surg.2017.10.003

Cited by 31 publications

(33 citation statements)

References 25 publications

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“…Osmotic pumps (Alzet ® 2004, Durect Corp., Cupertino, California) containing Ang II (1000 ng/kg/min, Sigma Aldrich Inc., St. Louis, Missouri) were introduced into 10 to 12 -week-old ZFP148 flx/flx, flx/wt and wt/wt ApoE−/− male mice as previously described 31, 36–39 . Mice were housed and maintained at 70°F, 50% humidity, in 12-hour light-dark cycles per institutional animal protocols.…”

Section: Methodsmentioning

confidence: 99%

ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Nuclear Factor 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation

Salmon

Schaheen

Spinosa

et al. 2019

ATVB

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Objective: The goal of this study was to determine the role of ZFP148 in aneurysm formation. Approach and Results: ZFP148 mRNA expression increased at day 3, 7, 14, 21 and 28 following during AAA formation in C57BL/6 mice. Loss of ZFP148 conferred AAA protection using ERTCre+ ZFP148 flx/flx mice. In a third set of experiments, smooth muscle specific loss of ZFP148 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt). Elastin degradation, LGAL3, and Neutrophil staining were significantly attenuated, while α-actin staining was increased in ZFP148 knock-out mice. Results were verified in total cell ZFP148 and smooth muscle specific knock-out mice using an Angiotensin II model, .ZFP148 smooth muscle specific conditional mice demonstrated increased proliferation and ZFP148 was shown to bind to the p21 promoter during AAA formation. ZFP148 smooth muscle specific conditional knock-out mice also demonstrated decreased apoptosis as measured by decreased cleaved Caspase-3 staining. ZFP148 bound smooth muscle marker genes via ChIP analysis mediated by NF-1 promote histone H3K4 de-acetylation via Histone De-acetylase 5. Transient transfections and ChIP analyses demonstrated that NF-1 was required for ZFP148 protein binding to Smooth Muscle marker genes promoters during aneurysm formation. Elimination of NF-1 using shRNA approaches demonstrated that NF-1 is required for binding and elimination of NF-1 increased BRG1 recruitment, the ATPase subunit of the SWI/SWF complex, and increased histone acetylation. Conclusions: ZFP148 plays a critical role in multiple murine models of aneurysm formation. These results suggest that ZFP148 is important in the regulation of proliferation, smooth muscle gene down-regulation and apoptosis in aneurysm development.

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Section: Methodsmentioning

confidence: 99%

ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Nuclear Factor 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation

Salmon

Schaheen

Spinosa

et al. 2019

ATVB

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Jiao

et al. 2020

European Journal of Vascular and Endovascular Surgery

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WHAT THIS PAPER ADDS Thoracic aortic dissection (TAD) is a life threatening cardiovascular disorder. Intermittent hypoxia (IH) triggers beneficial effects in multiple physiological systems, such as hypertension and coronary heart disease, in clinical and animal models. It was found that IH alleviates b-aminopropionitrile monofumarate induced TAD in C57BL/6 mice. Future studies should focus on the specific mechanism of thez protective role of IH and whether IH might be a treatment method for TAD. Objective: Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. Methods: b-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n ¼ 30) (21%e5% O 2 , 90 s/cycle, 10 h/day, IH þ BAPN group) or normoxia (n ¼ 30) (21% O 2 , 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O 2)/re-oxygenation (30 min, 21% O 2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1a and LOX via HIF-1a-siRNA. Results: It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1b, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1a. Conclusion: The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.

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“…However, aneurysms in these models either do not dissect or rupture (Ikonomidis et al, 2003;Pope et al, 2015), or do so at an extremely low rate (<20%; Li et al, 2014;Rateri et al, 2014;Yang et al, 2016). A few studies (Fashandi et al, 2018;Izawa-Ishizawa et al, 2019;Kanematsu et al, 2010;Kurihara et al, 2012) attempted to create a better model by modifying the traditional AngII protocol with the addition of β-aminopropionitrile (BAPN).…”

Section: Introductionmentioning

confidence: 99%

“…The modified protocols either boosted the rupture to an extremely high rate (>90%; Fashandi et al, 2018;Kurihara et al, 2012) or only marginally enhanced the rate of rupture (Hirakata et al, 2020;Izawa-Ishizawa et al, 2019;Kanematsu et al, 2010). Additionally, none of these studies determined whether this modified version is capable of recapitulating sex-dependent differences in AAD formation, as in the parent AngII model (Alsiraj et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…However, aneurysms in these models either do not dissect or rupture (Ikonomidis et al., 2003; Pope et al., 2015), or do so at an extremely low rate (<20%; Li et al., 2014; Rateri et al., 2014; Yang et al., 2016). A few studies (Fashandi et al., 2018; Izawa‐Ishizawa et al., 2019; Kanematsu et al., 2010; Kurihara et al., 2012) attempted to create a better model by modifying the traditional AngII protocol with the addition of β‐aminopropionitrile (BAPN). The modified protocols either boosted the rupture to an extremely high rate (>90%; Fashandi et al., 2018; Kurihara et al., 2012) or only marginally enhanced the rate of rupture (Hirakata et al., 2020; Izawa‐Ishizawa et al., 2019; Kanematsu et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

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A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs)

Wang

Chun

et al. 2020

Physiol Rep

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Fewer females develop AADs (ascending aortic aneurysms and dissections) and the reasons for this protection remain poorly understood. The present study seeks to develop a mouse model that may be utilized to address this sexual dimorphism. Adult normolipidemic mice were challenged with BAPN (β‐aminopropionitrile), AngII (angiotensin II), or BAPN + AngII. An initial protocol optimization found that 0.2% BAPN in drinking water plus AngII‐infusion at 1,000 ng kg−1 min−1 produced favorable rates of AAD rupture (~50%) and dilation (~40%) in 28 days. Using these dosages, further experiments revealed that BAPN is toxic to naïve mature aortas and it acted synergistically with AngII to promote aortic tears and dissections. BAPN + AngII provoked early infiltration of myeloid cells and subsequent recruitment of lymphoid cells to the aortic wall. AADs established with BAPN + AngII, but not AngII alone, continued to expand after the cessation of AngII‐infusion. This indefinite growth precipitated a 61% increase in the AAD diameter in 56 days. More importantly, with the optimized protocol, significant differences in AAD dilation (p = .012) and medial degeneration (p = .036) were detected between male and female mice. Treatment of ovariectomized mice with estradiol protected AAD formation (p = .014). In summary, this study developed a powerful mouse AAD model that can be used to study the sexual dimorphism in AAD formation.

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A novel reproducible model of aortic aneurysm rupture

Cited by 31 publications

References 25 publications

ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Nuclear Factor 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation

ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Nuclear Factor 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation

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

A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs)

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