Vitamin E Inhibits Abdominal Aortic Aneurysm Formation in Angiotensin II–Infused Apolipoprotein E–Deficient Mice

Gavrila, Dan; Li, Wei Gen; McCormick, Michael L.; Thomas, M.; Daugherty, Alan; Cassis, Lisa A.; Miller, Francis J.; Oberley, Larry W.; Dellsperger, Kevin C.; Weintraub, Neal L.

doi:10.1161/01.atv.0000172631.50972.0f

Cited by 157 publications

(53 citation statements)

References 49 publications

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“…Consistent with previous reports [13, 19], we demonstrated focal aortic dilatation within the suprarenal region in ApoE –/– mice infused with AngII. Concentrations of OPG detected within suprarenal aortic tissue of these animals were significantly higher than in corresponding tissue from ApoE –/– mice not infused with AngII.…”

Section: Discussionsupporting

confidence: 93%

“…A number of murine models of AAA have been developed [13,16,17,18]. The ApoE –/– mouse develops focal weakening primarily affecting the suprarenal aorta when infused subcutaneously with AngII [13, 19]. A limiting factor in this model is that formation of aortic aneurysm often involves destruction of the internal elastic lamina and focal dissection of the aortic wall rather than the circumferential medial destruction seen in human AAA [20].…”

Section: Discussionmentioning

confidence: 99%

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Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-γ in Abdominal Aortic Aneurysm

et al. 2008

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Background and Aims: Osteoprotegerin (OPG) has been associated with abdominal aortic aneurysm (AAA) expansion. Angiotensin II (AngII) receptor blockade has been shown to reduce OPG expression in human AAA tissue. Interaction between vascular AngII and OPG was further examined using cell culture and the AngII-infused ApoE^–/– mouse AAA model. The ability of peroxisome proliferator-activated receptor-γ (PPARγ) activation to target OPG as potential therapy for AAA was also investigated. Methods and Results: Human aortic smooth muscle cells (AoSMC) exposed to AngII exhibited dose-dependent increase in the production OPG. A 3-fold increase in suprarenal aortic concentration of OPG was observed in AngII-infused ApoE^–/– mice. AngII type 1 receptor expression in human AAA tissue, and AoSMC in vitro, was stimulated up 4-fold in the presence of OPG. This effect in AoSMC was counteracted in the presence of the PPARγ ligand, pioglitazone. Addition of PPARγ ligand to cultured human AAA explant reduced OPG secretion by 60% and tissue concentration of OPG and metalloproteinase 9 by 2- and 3-fold, respectively. Administration of pioglitazone to AngII-infused ApoE^–/– mice significantly reduced aortic concentrations of OPG and metalloproteinase 9. Conclusions: These data support an interaction between AngII and OPG in aneurysm formation. Activation of PPARγ may have a role in treatment of AAA.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-γ in Abdominal Aortic Aneurysm

et al. 2008

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“…Many recent studies have also demonstrated that AngII induces AAAs in normolipidemic mice [5][6][7] . The approach of infusing AngII has been applied to induce AAAs and explore molecular mechanisms as well as development of potential therapeutic strategies (e.g., [5][6][7][8][9][10][11][12][13][14][15] ) since this model recapitulates many features observed in human AAAs. For example, risk factors of human AAAs such as smoking, aging, and male gender also augment AngII-induced AAAs in mice 16,17 .…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Lü

Howatt

Balakrishnan

et al. 2015

JoVE

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Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5 -10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms.

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“…In addition, previous studies have reported that antioxidant subjects inhibit AAA formation via attenuation of MMP activity in murine AAA models. [19][20][21] Therefore, oxidative stress is considered to be one of the therapeutic targets for AAA. However, it is well known that iron is a powerful mediator of oxidative stress.…”

mentioning

confidence: 99%

Aortic Iron Overload With Oxidative Stress and Inflammation in Human and Murine Abdominal Aortic Aneurysm

Sawada

Hao

Naito

et al. 2015

ATVB

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A bdominal aortic aneurysm (AAA) is a common vascular disease, which occurs in ≈4% to 8% of men aged 65 to 80 years.1 Aortic rupture is the most feared clinical consequence of AAA progression, resulting in mortality in ≈90% of cases. [2][3][4] Because AAA usually progresses without symptoms, AAA is often discovered in advanced stage. At present, surgical aortic replacement and endovascular stent graft repair are performed as standard definitive therapies for AAA. However, there is no effective medical therapy to prevent aortic rupture in AAA. Although several studies have reported the pathophysiology of AAA, the mechanisms of AAA formation are largely unknown. Therefore, it is necessary to investigate the molecular pathophysiology of AAA to find noninvasive strategies for the prevention of AAA.Iron is an essential element for maintaining physiological function. However, excess iron causes tissue damage by oxidative stress via the Fenton/Haber-Weiss reaction. 5Therefore, iron is involved in the pathophysiology of several diseases including cardiovascular diseases. In fact, we have previously shown that iron accumulation and superoxide production are observed in the renal tubules of a rat model of chronic kidney disease.6 Lee et al 7 have shown that iron accumulation is observed in the atherosclerotic lesions of apolipoprotein E knockout mice. Most recently, Martinez-Pinna et al 8 have demonstrated that iron is deposited in human AAA walls. Meanwhile, we have also reported that dietary iron restriction (IR) prevents the development of hypertension and proteinuria with inhibition of oxidative stress and inflammation in Dahl salt-sensitive hypertensive rats.9 Although oxidative stress and inflammation are well known to be involved in the development of AAA formation, it has not been investigated whether iron is associated with the pathophysiology of AAA through © 2015 American Heart Association, Inc. Objective-Although iron is an essential element for maintaining physiological function, excess iron leads to tissue damage caused by oxidative stress and inflammation. Oxidative stress and inflammation play critical roles for the development of abdominal aortic aneurysm (AAA). However, it has not been investigated whether iron plays a role in AAA formation through oxidative stress and inflammation. We, therefore, examined whether iron is involved in the pathophysiology of AAA formation using human AAA walls and murine AAA models. Approach and Results-Human aortic walls were collected from 53 patients who underwent cardiovascular surgery (non-AAA=34; AAA=19). Murine AAA was induced by infusion of angiotensin II to apolipoprotein E knockout mice. Iron was accumulated in human and murine AAA walls compared with non-AAA walls. Immunohistochemistry showed that both 8-hydroxy-2′-deoxyguanosine and CD68-positive areas were increased in AAA walls compared with non-AAA walls. The extent of iron accumulated area positively correlated with that of 8-hydroxy-2′-deoxyguanosine expression area and macrophage infiltration area in huma...

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Vitamin E Inhibits Abdominal Aortic Aneurysm Formation in Angiotensin II–Infused Apolipoprotein E–Deficient Mice

Cited by 157 publications

References 49 publications

Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-γ in Abdominal Aortic Aneurysm

Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-γ in Abdominal Aortic Aneurysm

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Aortic Iron Overload With Oxidative Stress and Inflammation in Human and Murine Abdominal Aortic Aneurysm

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