Abstract 341: Cytochrome P450 1b1 Is Essential For The Development Of Aortic Aneurysm In Apoe Knockout Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Shyamala Thirunavukkarasu ◽  
Nayaab S Khan ◽  
Hafiz U Ghafoor ◽  
Brett L Jennings ◽  
Kamalika Mukherjee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Gene Deletion ◽  
Growth Factor Receptor ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Simultaneous Treatment ◽  
Markers Of Inflammation ◽  
Cyp1b1 Gene ◽  
Abdominal Aortic

Previously we showed that the development of hypertension is dependent on cytochrome P450 (CYP)1B1 activity. This study addressed the role of CYP1B1 in the pathogenesis of angiotensin II (Ang II)-induced aortic aneurysms. Sixteen week old male ApoE-/-/Cyp1b1+/+ and ApoE-/-/Cyp1b1-/- mice were administered Ang II (700 ng/min/Kg) or its vehicle (veh) for one month using mini-osmotic pumps implanted subcutaneously. A separate group of ApoE-/-/Cyp1b1+/+ mice receiving Ang II were injected twice weekly with the selective inhibitor of CYP1B1 2,3',4,5'-tetramethoxystilbene (TMS) (300 μg/Kg) or its vehicle DMSO (i.p.). Ultrasound studies showed that Ang II infusion produced abdominal aortic aneurysms in the ApoE-/-/Cyp1b1+/+ mice that were prevented by simultaneous treatment with TMS or Cyp1b1 gene deletion. Ang II-induced aortic aneurysms were characterized by increased degradation of collagen, elastin and actin; and expression of matrix metalloproteinases MMP2, 9 as well as markers of inflammation including macrophages, and CD3+ T cells, and increased production of reactive oxygen species in the ApoE-/-/Cyp1b1+/+ mice; these changes were minimized by treatment with TMS or Cyp1b1 gene deletion (Table 1). Microarray analysis indicated downregulation (>1.5 fold) of markers of angiogenesis and inflammation including Angiopoeitin 2, P-selectin, platelet derived growth factor receptor, MMP 2, 9 and 12, and CD276 in the ApoE-/-/Cyp1b1-/- mice. These data suggest that Ang II-induced abdominal aortic aneurysms and associated pathophysiological changes in ApoE-/- mice are mediated by CYP1B1 via increased inflammation and oxidative stress.

scholarly journals Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe –/– Male Mice

2021 ◽  
Author(s):  
Kamalika Mukherjee ◽  
Ajeeth K. Pingili ◽  
Purnima Singh ◽  
Ahmad N. Dhodi ◽  
Shubha R. Dutta ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Risk Factor ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Abdominal Aortic ◽  
Induced Hypertension

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe –/– male mice. Methods and Results Intact or castrated Apoe –/– /Cyp1b1 +/+ and Apoe –/– /Cyp1b1 –/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe –/– /Cyp1b1 +/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe –/– /Cyp1b1 –/– mice. Conclusions Our results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe –/– male mice.

Abstract 18182: Phosphodiesterase 10A Regulates Vascular Inflammation and Pathogenesis of Abdominal Aortic Aneurysms

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yujun Cai ◽  
Yujun Cai ◽  
Chen Yan ◽  
Raul J Guzman
Keyword(s):  
Vascular Inflammation ◽  
Critical Role ◽  
Abdominal Aortic Aneurysms ◽  
Peritoneal Macrophages ◽  
Aortic Aneurysms ◽  
Causative Role ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Abdominal Aortic

Rationale: Abdominal aortic aneurysms (AAA) are characterized by aortic enlargement and underlying weakness of the vessel wall. Experimental and clinical evidence suggests that vascular inflammation is a central trigger of AAA formation. Phosphodiesterases (PDEs), known regulators of cyclic nucleotide signaling, play a critical role in vascular inflammation. Objective: In this study, we sought to determine the role and function of PDE10A in vascular inflammation and AAA formation. Methods and Results: Extensive evidence suggests that angiotensin II (Ang II) signaling plays an important causative role in AAA formation. Therefore, Real-time PCR array for all 22 known PDE genes was performed in control and Ang II-treated VSMCs. We observed that PDE10A elicited the highest levels of induction by Ang II among all PDEs. Moreover, we found that PDE10A was dramatically upreguated in the Ang II-infused AAA mouse model and in human AAA specimens. PDE10A was primarily expressed in medial VSMCs and infiltrating macrophages in AAA. More importantly, deficiency of PDE10A or PDE10A inhibition significantly attenuated AAA formation in vivo. In cultured VSMCs, knockdown of PDE10A with specific siRNA and inhibition of PDE10A by papaverine markedly suppressed Ang II-induced vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and MMP2 expression. Deficiency of PDE10A also blocked lipopolysaccharide (LPS)-induced TNF-α, MCP-1, and MMP9 expression in peritoneal macrophages isolated from PDE10A knockout mice. Further mechanistic studies revealed that histone deacetylase 5 (HDAC5) plays an important role in PDE10A-regulated vascular inflammation via cAMP-dependent protein kinase (PKA). Conclusions: These findings demonstrate that PDE10A is an important regulator of vascular inflammation and AAA development. They further provide evidence for PDE10A as a potential therapeutic target for aortic aneurysms and other vascular diseases.

scholarly journals ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice

2009 ◽  
Vol 296 (5) ◽  
pp. H1660-H1665 ◽  
Author(s):  
Lisa A. Cassis ◽  
Manisha Gupte ◽  
Sarah Thayer ◽  
Xuan Zhang ◽  
Richard Charnigo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ldl Receptor ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Similar Extent ◽  
Atherosclerotic Lesions ◽  
Abdominal Aortic ◽  
Blood Pressures ◽  
Deficient Mice

Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng·kg−1·min−1) or norepinephrine (NE; 5.6 mg·kg−1·day−1) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 ± 2.8; NE, 129 ± 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 ± 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE−/−) or LDLr-deficient (LDLr−/−) mice infused with ANG II (apoE−/−: 1.4 ± 0.1; LDLr−/−: 1.6 ± 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE−/−: 0.91 ± 0.03; LDLr−/−: 0.87 ± 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng·kg−1·min−1), AAAs developed in 50% of apoE−/− mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE−/− mice (1,000 ng·kg−1·min−1) lowered systolic blood pressure ( day 28: ANG II, 157 ± 6; ANG II/hydralazine, 135 ± 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.

scholarly journals The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms

2012 ◽  
Vol 303 (8) ◽  
pp. H1067-H1075 ◽  
Author(s):  
Ebony Washington Remus ◽  
Robert E. O'Donnell ◽  
Kathryn Rafferty ◽  
Daiana Weiss ◽  
Giji Joseph ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Lysyl Oxidase ◽  
Family Members ◽  
Atherosclerotic Lesion ◽  
Abdominal Aortic Aneurysms ◽  
The United States ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Polymeric Scaffold ◽  
Abdominal Aortic

Abdominal aortic aneurysms (AAAs) are a major cause of morbidity and mortality in the United States today. We employed a model for AAA development using apolipoprotein E knock out mice fed a high-fat diet and treated with ANG II and β-aminopropionitrile (β-APN) for 4 wk. ANG II induces hypertension and atherosclerotic disease, whereas β-APN inhibits the activity of the lysyl oxidase/ lysyl oxidase-like protein (LOX/LOXL) family members. LOX/LOXL family members crosslink collagen and elastin in the extracellular matrix and therefore contribute to the integrity and stabilization of a healthy vessel wall. In this model, cotreatment with ANG II and β-APN caused a 90% AAA incidence and increased atherosclerotic lesion formation from less than 5% to greater than 25% after 4 wk. In more atheroprotected mouse strains (C57BL/6 and BalbC), cotreatment with ANG II and β-APN caused 50% and 40% AAA incidence, respectively. These data demonstrate the importance of LOX/LOXL to the stability of the vessel wall. Therapeutic strategies to overexpress LOX/LOXL enzymes or to support the crosslinking of soluble matrix proteins in a polymeric scaffold are a promising opportunity to achieve stabilization of AAAs.

scholarly journals Alterations in gut microbiota of abdominal aortic aneurysm mice

2019 ◽  
Author(s):  
Jiahe Xie ◽  
Weiling Lu ◽  
Lintao Zhong ◽  
Yuhua Hu ◽  
Qingrui Li ◽  
...  
Keyword(s):  
16S Rrna ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Microbial Dysbiosis ◽  
Abdominal Aortic ◽  
Rrna Sequencing ◽  
Taxonomic Groups

Abstract Background：The gut microbiome plays an important role in various cardiovascular diseases, such as atherosclerosis and hypertension, which are associated with abdominal aortic aneurysms (AAAs). Methods: Here, we used 16S rRNA sequencing to explore gut microbiota in C57BL ApoE-/- mice with AAAs. A mouse model of abdominal aortic aneurysms was induced with angiotensin II (Ang II) (1000 ng/min per kg). On day 28 after the operation, fecal samples were collected and stored at −80 °C until DNA extraction. We determined the relative abundances of bacterial taxonomic groups using 16S rRNA amplicon metabarcoding, and sequences were analyzed using a combination of mother software and UPARSE. Results: We found that the gut microbiome was different between control and AAA mice. The results of correlation analysis between AAA diameter and the gut microbiome as well as LEfSe of the genera Akkermansia, Odoribacter, Helicobacter and Ruminococcus might be important in the progression of AAAs. Conclusions: AAA mice is subjected to gut microbial dysbiosis, and gut microbiota might be a potential target for further investigation.

scholarly journals Weight loss in obese C57BL/6 mice limits adventitial expansion of established angiotensin II-induced abdominal aortic aneurysms

2010 ◽  
Vol 298 (6) ◽  
pp. H1932-H1938 ◽  
Author(s):  
Sara B. Police ◽  
Kelly Putnam ◽  
Sean Thatcher ◽  
Frederique Batifoulier-Yiannikouris ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Weight Loss ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Stem Cell Marker ◽  
Ang Ii ◽  
Low Fat Diet ◽  
Abdominal Aortic ◽  
Induce Weight Loss ◽  
Adipose Derived Stem Cell

Previous studies demonstrated that obesity increases inflammation in periaortic adipose tissue and promotes angiotensin II (ANG II)-induced abdominal aortic aneurysms (AAAs). We sought to determine whether weight loss of obese C57BL/6 mice would influence the progression of established AAAs. Male C57BL/6 mice were fed a high-fat diet (HF) for 4 mo and then infused with either saline or ANG II (1,000 ng·kg−1·min−1) for 3 mo. Mice with dilated suprarenal aortas at 28 days of ANG II infusion were designated to groups fed the HF (HF/HF) or a low-fat diet (LF; 10% kcal as fat; HF/LF) to induce weight loss for the last 2 mo of infusions. Suprarenal aortic lumen diameters of obese mice were increased by ANG II infusion at day 28 ( day 0: 1.03 ± 0.02; day 28: 1.86 ± 0.14 mm; P < 0.05), but did not progress with continued infusion in HF/HF mice. Moreover, aortic lumen diameters were not different between groups (HF/HF: 1.89 ± 0.15; HF/LF: 1.79 ± 0.18 mm). However, maximal diameters of excised AAAs were decreased with weight loss (HF/HF: 2.00 ± 0.11; HF/LF: 1.55 ± 0.13 mm; P < 0.05) and had reduced adventitial areas (HF/HF: 1.18 ± 0.10; HF/LF: 0.54 ± 0.02 mm2; P < 0.05). Neovascularization of aortic adventitias was strikingly decreased in HF/LF mice (HF/HF: 43 ± 5; HF/LF: 12 ± 2 endothelial cells/adventitial area; P < 0.05). ANG II-induced elevations in adipose mRNA abundance of CD105, an adipose-derived stem cell marker, were abolished with weight loss. These results demonstrate that weight loss limits adventitial expansion of ANG II-induced AAAs. Reduced neovascularization from weight loss may limit progression of AAAs.

Ruptured abdominal aortic aneurysms: Clinical presentation in Auckland 1993-1997

2001 ◽  
Vol 71 (6) ◽  
pp. 341-344
Author(s):  
Johanna Rose ◽  
Ian Civil ◽  
Timothy Koelmeyer ◽  
David Haydock ◽  
Dave Adams
Keyword(s):  
Clinical Presentation ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Ruptured Abdominal Aortic Aneurysms

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Diehm ◽  
Schmidli ◽  
Dai-Do ◽  
Baumgartner
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Medical Treatment ◽  
Endovascular Treatment ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Current Evidence ◽  
Significant Morbidity ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

Sign in / Sign up

Export Citation Format

Share Document