Abstract 283: Platelet Inhibition Increases Angiotensin II-induced Abdominal Aortic Aneurysm Incidence and Rupture in Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
A. Phillip Owens ◽  
Yacine Boulaftali ◽  
Wolfgang Bergmeier ◽  
James P Luyendyk ◽  
Nigel Mackman
Keyword(s):  
Angiotensin Ii ◽  
Mouse Model ◽  
Milk Fat ◽  
Aortic Rupture ◽  
Plasma Cholesterol ◽  
Dabigatran Etexilate ◽  
Aortic Aneurysms ◽  
Thrombin Inhibitor ◽  
Drug Bioavailability ◽  
Abdominal Aortic

Objective Platelets play a central role in both hemostasis and thrombosis. The coagulation protease thrombin activates platelets by cleavage of protease-activated receptors (PAR1 and PAR4 in humans, and PAR3 and PAR4 in mice). Circulating thrombin is increased in patients with abdominal aortic aneurysms (AAAs). We recently demonstrated that PAR4 deficiency in mice increased the incidence of aneurysm (P = 0.001) and rupture-induced death (P = 0.003) in an angiotensin II (AngII) infusion model of AAA. Furthermore, platelet depletion significantly increased rupture in this model (P = 0.048). The purpose of this study was to examine clinically used anti-platelet drugs in this mouse model of AAA. Methods and Results Male Ldlr -/- mice (8-12 weeks in age) were fed a fat and cholesterol-enriched diet (21% milk fat, 0.2% cholesterol). Groups of mice received either aspirin (30 mg/L via drinking water [ASA]), or diet supplemented with the direct thrombin inhibitor dabigatran etexilate (10 g/kg chow [DE]) or the P2Y 12 inhibitor clopidogrel (50 mg/kg/day [Plavix]) 1 week prior to and throughout AngII (1,000 ng/kg/min) infusion for 28 days. Drug bioavailability was confirmed with all treatments. Medial diameters in the suprarenal aortic region were increased significantly from baseline to day 28 in all groups infused with AngII, as measured by in vivo ultrasound. Medial diameters were not different in any of the treatment groups compared with placebo controls. However, DE (87% vs. 47%) and Plavix (82% vs. 40%) significantly increased the incidence of AAA versus placebo groups (P < 0.05). ASA also increased the incidence of AAA (93% vs. 70% P = NS). Importantly, all treatments had a significant increase in aortic rupture-induced death versus placebo groups (P < 0.05; DE [67% vs. 7%]; Plavix [41% vs. 0%]; and ASA [64% vs. 10%]). None of the treatments affected total plasma cholesterol, lipoprotein-cholesterol distributions, or AngII-induced increases in systolic blood pressure. Conclusion This study indicates that the presence of functional platelets reduces the formation and rupture of AAA in this mouse model. This suggests that inhibition of platelet function may be detrimental to patients with existing AAAs, a conclusion that will be addressed in future mouse studies.

Abstract 522: TGF-beta Neutralization Augments Development of Angiotensin II-induced Aneurysms in Both Ascending and Abdominal Aortic Regions

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Xiaofeng Chen ◽  
Debra L Rateri ◽  
Deborah A Howatt ◽  
Anju Balakrishnan ◽  
Jessica J Moorleghen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transforming Growth Factor Beta ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Aortic Rupture ◽  
Neutralizing Antibody ◽  
Normal Diet ◽  
Aortic Aneurysms ◽  
Tgf Beta ◽  
Abdominal Aortic

Introduction and Objectives Angiotensin II (AngII) infusion induces ascending and abdominal aortic aneurysms (AAs) in mice. In a mouse model of Marfan Syndrome expressing Fbn1 C1039G/+ , ascending AAs were reduced by administration of a transforming growth factor-beta (TGF-beta) neutralizing antibody. In contrast, administration of TGF-beta neutralizing antibodies to AngII-infused mice increased aortic rupture. The purpose of this study was to compare the effects of TGF-beta neutralization on formation and progression of AngII-induced ascending and abdominal AAs. Methods and Results Male C57BL/6 mice were fed a normal diet and infused subcutaneously with AngII (1,000 ng/kg/min). Five days prior to initiating infusion, mice were injected i.p. with either a mouse monoclonal TGF-beta antibody (1D11) or an isotype matched IgG at a dose of either 0.3 or 5 mg/kg x 3/per week. 1D11 administration significantly decreased serum TGF-beta concentrations. TGF-beta neutralization at 5 mg/kg greatly increased the incidence of aortic rupture, which was attributed to rupture in both the ascending and abdominal regions. For mice that remained viable after 28 days of infusion, there were equivalent increases in aortic dilation in both the ascending and abdominal regions. Prior to rupture, aortic diameters determined by ultrasound demonstrated no significant effect on AngII-induced dilation of the ascending or abdominal aorta. We also studied the effects of TGF-beta neutralization in mice with established AngII-induced AAs following AngII-infusion for 28 days. C57BL/6 mice were injected with the mouse TGF-beta neutralizing antibody or IgG control (5 mg/kg x 3/per week, n=10 per group), while AngII infusion was continued for a further 28 days. Although TGF-beta antibody administration significantly decreased serum TGF-beta concentrations in mice with established AAs, there was no effect on aortic rupture or dilation of either the ascending or abdominal aortic region. Conclusion TGF-beta inhibition augmented AngII-induced aortic rupture in both the ascending and abdominal regions but had no effect on dilation. Furthermore, TGF-beta neutralization had no effect on either aortic rupture or expansion in established AAs.

Abstract 101: Characteristics of Angiotensin II-induced Abdominal Aortic Aneurysms in Selected Mouse Strains Expressing PCSK9D377Y

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Anju Balakrishnan ◽  
Deborah A Howatt ◽  
Alan Daugherty ◽  
Hong Lu
Keyword(s):  
Angiotensin Ii ◽  
Viral Vector ◽  
Plasma Cholesterol ◽  
Ldl Receptor ◽  
Abdominal Aortic Aneurysms ◽  
Western Diet ◽  
Aortic Aneurysms ◽  
Mouse Strains ◽  
Gain Of Function ◽  
Abdominal Aortic

Objective: Our previously study demonstrated that infection of C57BL/6 mice with an adeno-associated viral vector (AAV) expressing the proprotein convertase subtilisin/kexin type 9 (PSCK)9D377Y gain-of-function mutant led to augmentation of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs). The purpose of this study was to optimize PCSK9D377Y expression in mice for AngII-induced AAA formation. We also determined the susceptibility of PCSK9D377Y expression to increase AngII-induced AAA in selected normolipidemic mouse strains. Methods and Results: To determine optimal dose for infection, C57BL/6 mice were injected intraperitoneally with AAVs containing either an empty vector or PCSK9 D377Y at three doses (3 x 10 10 , 10 x 10 10 , or 30 x 10 10 genomic copies/mouse). Mice were fed a Western diet for 6 weeks starting immediately after AAV injections. Two weeks after AAV injection, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. Plasma PCSK9 concentrations were increased dose-dependently in mice injected with AAV containing PCSK9D377Y mutation, accompanied by increased plasma cholesterol concentrations. Infection with the intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas. Therefore, the intermediate dose was used in the following experiments. Effects of PCSK9 D377Y.AAV infection was then determined in 5 normolipidemic mouse strains (C57BL/6, 129, FVB, DBA/2, and BALB/c). C57BL/6 mice were the most susceptible to AAV infection, whereas BALB/c mice were completely resistant. Consistently, C57BL/6 mice with increased plasma cholesterol concentrations had higher AngII-induced AAA formation. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male LDL receptor -/- mice fed the same Western diet. Although plasma total cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV than LDL receptor -/- mice, these two mouse strains had equivalent AAA formation. Conclusions: This study provided evidence that C57BL/6 mouse strain was the most susceptible strain to AAV-driven expression of a gain of function mutant of PCSK9 that promoted AngII-induced AAAs to an equivalent incidence as LDL receptor -/- mice.

scholarly journals Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice

2010 ◽  
Vol 118 (11) ◽  
pp. 681-689 ◽  
Author(s):  
Alan Daugherty ◽  
Debra L. Rateri ◽  
Israel F. Charo ◽  
A. Phillip Owens ◽  
Deborah A. Howatt ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Chemokine Receptor ◽  
Plasma Cholesterol ◽  
Ascending Aorta ◽  
Aortic Aneurysms ◽  
Whole Body ◽  
Abdominal Aortic ◽  
Aortic Media ◽  
The Media ◽  
Medial Thickening

AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)−/− mice that were either CCR2+/+ or CCR2−/−, were infused with either saline or AngII (1000 ng·kg−1 of body weight·min−1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE−/− mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency.

scholarly journals Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoying Wang ◽  
Vaideesh Parasaram ◽  
Saphala Dhital ◽  
Nasim Nosoudi ◽  
Shahd Hasanain ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cause Of Death ◽  
Targeted Delivery ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Systemic Delivery ◽  
Effective Treatment Option ◽  
Abdominal Aortic ◽  
Pentagalloyl Glucose ◽  
Elastic Lamina

AbstractAbdominal aortic aneurysm (AAA) disease causes dilation of the aorta, leading to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and 10th leading cause of death in men over age 55, affecting thousands of patients. Despite the prevalence of AAA, no safe and efficient pharmacotherapies exist for patients. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs, making it an ideal target for delivering drugs to the AAA site. In this research, we conjugated nanoparticles with an elastin antibody that only targets degraded elastin while sparing healthy elastin. After induction of aneurysm by 4-week infusion of angiotensin II (Ang II), two biweekly intravenous injections of pentagalloyl glucose (PGG)-loaded nanoparticles conjugated with elastin antibody delivered the drug to the aneurysm site. We show that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastic lamina, and improve the mechanical properties of the aorta at the AAA site. Therefore, simple iv therapy of PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to reverse disease progression and return the aorta to normal homeostasis.

scholarly journals Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e49642 ◽  
Author(s):  
Yasunori Iida ◽  
Baohui Xu ◽  
Geoffrey M. Schultz ◽  
Vinca Chow ◽  
Julie J. White ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Receptor Blocker ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Abdominal Aortic

Abstract 1684: Toll-like Receptor 4 Deficiency Attenuates Angiotensin II-induced Atherosclerosis and Abdominal Aortic Aneurysms via a MyD88-dependent Mechanism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
A. Phillip Owens ◽  
Deborah A Howatt ◽  
Alan Daugherty
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Atherosclerotic Lesion ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Vascular Pathology ◽  
Toll Like Receptor ◽  
Abdominal Aortic ◽  
Post Infusion

Objective: We previously demonstrated that angiotensin II (AngII) infusion into myeloid differentiation factor 88 deficient mice (MyD88−/−) resulted in a profound reduction of atherosclerosis and abdominal aortic aneurysms (AAAs) in apoE−/− mice. Furthermore, AngII directly regulated toll-like receptor (TLR) mRNA in cell types associated with these diseases. The objective of this study was to determine the specific TLR responsible for the MyD88 mediated reduction in vascular pathology. Methods and Results: MyD88 mice were bred onto an LDLr−/− background. Deficiency in this hyperlipidemic strain caused similar decreases in AngII-induced atherosclerosis and aneurysm to those we previously noted in apoE−/− mice. Male TLR4+/+ (n = 14) or −/− (n = 19), on an LDLr−/− background, were fed a fat-enriched diet (21% milk fat, 0.15% cholesterol) and infused with AngII (1,000ng/kg/min) for 28 days. TLR4−/− mice had significantly attenuated systolic blood pressure from TLR4+/+ mice both prior to and during AngII infusion (P < .01). However, AngII did increase systolic blood pressure similarly in both groups (+/+: pre-infusion 142 ± 2, post-infusion 169 ± 3 mmHg; −/−: pre-infusion 130 ± 1, post-infusion 158 ± 3 mmHg; P < .001). Neither TLR4 genotype nor AngII infusions had significantly different effects on total plasma cholesterol concentrations or lipoprotein-cholesterol distributions. TLR4 deficiency dramatically decreased AngII-induced atherosclerotic lesion areas in both the aortic arch (50% decrease, P < .004), and thoracic aorta (66% decrease, P < .001). TLR4 deficiency decreased the diameter of the suprarenal abdominal aortic region from 2.31 ± 0.3 to 1.2 ± 0.06 mm (P < 0.001) and the incidence of AAAs from 93% to 26% (P < 0.001), versus control animals. Conversely, TLR2 deficiency reduced AngII-induced atherosclerosis in LDLr−/− mice, but had no significant effect on AAA formation. Conclusion: TLR4 deficiency attenuated both AngII-induced atherosclerosis and AAAs, in LDLr−/− mice, in a manner similar to the effects of MyD88 deficiency. TLR2 deficiency decreased AngII-induced atherosclerosis, but had no effect on AAAs. These data are consistent with TLR4 being the major receptor for MyD88-induced effects on AngII-induced AAAs. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

scholarly journals GSDMD Deficiency Protects Against Aortic Rupture

2021 ◽  
Author(s):  
Dien Ye ◽  
Deborah Howatt ◽  
Zhenyu Li ◽  
Alan Daugherty ◽  
Hong S. Lu ◽  
...  
Keyword(s):  
Drinking Water ◽  
Viral Vectors ◽  
Aortic Rupture ◽  
Initial Study ◽  
Aortic Aneurysms ◽  
Aortic Dilation ◽  
Abdominal Aortic ◽  
Aortic Pathologies ◽  
Deficient Mice ◽  
Macrophage Accumulation

Objective: Aortic ruptures are fatal consequences of aortic aneurysms with macrophage accumulation being a hallmark at the site of ruptures. Pyroptosis is critical in macrophage-mediated inflammation. This study determined effects of pyroptosis on aortic dilation and rupture using GSDMD deficient mice. Approach and Results: In an initial study, male Gsdmd+/+ and Gsdmd-/- mice in C57BL/6J background (8 to 10 weeks old) were infected with adeno-associated viral vectors encoding mouse PCSK9D377Y gain-of-function mutation and fed a Western diet to induce hypercholesterolemia. After two weeks of AAV infection, angiotensin II (AngII, 1,000 ng/kg/min) was infused. During the 4 weeks of AngII infusion, 5 of 13 Gsdmd+/+ mice died of aortic rupture, whereas no aortic rupture occurred in Gsdmd-/- mice. In surviving mice, no differences in either ascending or abdominal aortic dilation were observed between Gsdmd+/+ and Gsdmd-/- mice. To determine whether protection of GSDMD deficiency against aortic rupture is specific to AngII infusion, we subsequently examined aortic pathologies in mice administered beta-aminopropionitrile (BAPN). BAPN (0.5% wt/vol) was administered in drinking water to male Gsdmd+/+ and Gsdmd-/- mice (4 weeks old) for 4 weeks. Six of 13 Gsdmd+/+ mice died of aortic rupture, whereas no aortic rupture occurred in Gsdmd-/- mice. In mice survived, no differences of diameters in the ascending, arch, or abdominal aortic regions were observed between Gsdmd+/+ and Gsdmd-/- mice. Conclusions: GSDMD deficiency protects against AngII or BAPN-induced aortic ruptures in mice.

scholarly journals Complement Regulator CD59 Protects Against Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

Circulation ◽  
2010 ◽  
Vol 121 (11) ◽  
pp. 1338-1346 ◽  
Author(s):  
Gongxiong Wu ◽  
Ting Chen ◽  
Aliakbar Shahsafaei ◽  
Weiguo Hu ◽  
Roderick T. Bronson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Complement Regulator
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