Abstract 418: Microfibrillar-Associated Protein 4 Deficiency Reduces Size and Incidence Rate of Angiotensin II Induced Abdominal Aortic Aneurysms in Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Katrine L Kirketerp-Møller ◽  
Jane Stubbe ◽  
Anders Schlosser ◽  
Karin Kejling ◽  
Jesper B Møller ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Incidence Rate ◽  
Aortic Aneurysms ◽  
Aortic Tissue ◽  
Aortic Blood Flow ◽  
Infrarenal Aorta ◽  
Arterial Blood ◽  
Elastin Degradation ◽  
Abdominal Aortic

Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein primarily located in elastic arteries. It can bind elastin and collagen, and furthermore activate vascular cells through cellular integrin binding and modulate matrix metalloprotinase (MMP) activity. We hypothesized that lack of MFAP4 would decrease vascular inflammation and abdominal aortic aneurysm (AAA) formation. AAA was induced in 9-11 week old mice using two experimental mouse models: 1) Male Mfap4 -/- /ApoE -/- double knock-out (dKO) and ApoE -/- littermate control mice were feed western diet and subjected to continuously angiotensin II (AngII, 1000 ng/kg/min) infusion for 9-28 days via subcutaneous osmotic mini-pumps. Arterial blood pressure was measured in the femoral artery. 2) 1.5 U/mL elastase was infused into the infrarenal aorta in Mfap4 -/- and littermate Mfap4 +/+ mice for 5 minutes. Aortic blood flow was restored and the mice recovered for 9-16 days. Aortic diameter was measured in mice subjected to AngII or elastase infusion at day 28 and 16 respectively. MMP activity was detected by zymography. No difference in AAA formation was observed between genotypes after elastase perfusion. In response to AngII infusion dKO mice showed a significantly decrease in AAA diameter and incidence rate compared to ApoE -/- mice. AngII-induced increase in blood pressure was not dependent of MFAP4. However, there was decreased aortic arch atherosclerotic plaque formation, MMP2 and MMP9 activity in aortic tissue from dKO mice compared to ApoE -/- mice. Furthermore there was a non-significant tendency of decreased elastin degradation score in the AngII infused dKO mice, however this was not observed in the elastase perfused mice. Activity of MMP12 and extent of infiltrating leukocytes in aneurysmal tissue from both models will be further investigated. In conclusion we observed a decreased AAA formation and MMP activity in Mfap4 -/- /ApoE -/- mice which was not explained by variation in blood pressure or altered elastin degradation. The data suggest that MFAP4 induces MMP2-activity and thus the propensity for AAA formation.

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).

Abstract 461: Cilnidipine Attenuated Angiotensin II-induced Abdominal Aortic Aneurysms in Apolipoprotein E-deficient Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yuki Kakio ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Jun Wada
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Apolipoprotein E ◽  
Ex Vivo ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Osmotic Minipumps ◽  
Abdominal Aortic ◽  
Deficient Mice

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, it is reported that voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Therefore, we hypothesized that cilnidipine, an N/L-type calcium channel blocker, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in mice. The purpose of this study was to evaluate whether cilnidipine influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) each by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. AngII infusion did not alter serum cholesterol concentrations. However, cilnidipine slightly decreased serumcholesterol concentrations in AngII-infused mice. Cilnidipine had no effect on body weights, heart rates, and urine total protein, but mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine did not affect ex vivo measurement of maximal diameter of abdominal aorta (1.04 ± 0.09 mm vs 1.11 ± 0.06 mm, n.s.) in saline infused mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas, but was attenuated by cilnidipine (1.79 ± 0.59 mm vs 1.26 ± 0.38 mm, P < 0.05). In addition, cilnidipine significantly reduced the incidence of AngII-induced AAAs (Cilnidipine: 38 %, Vehicle: 88 %; P < 0.05). Furthermore, gelatin zymography demonstrated that cilnidipine diminished AngII-induced increase in aortic MMP-9 protein abundance. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

Abstract 104: Cilnidipine Attenuated Angiotensin II-induced Abdominal Aortic Aneurysms in Apolipoprotein E-deficient Mice via Its Anti-oxidative Stress Effect

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yuki Kakio ◽  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Jun Wada
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Apolipoprotein E ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Stress Effect ◽  
Osmotic Minipumps ◽  
Abdominal Aortic ◽  
Deficient Mice

Objective: Chronic angiotensin II (AngII) infusion promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, voltage-dependent N-type Ca 2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Last year, we reported that cilnidipine, an N/L-type calcium channel blocker, attenuated AngII-induced AAAs in apolipoprotein E deficient mice. The purposed of this study was to determine the mechanism of cilnidipine reducing AngII-induced AAAs Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. Cilnidipine mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine mildly decreased plasma aldosterone concentrations that were increased by AngII infusion. Cilnidipine significantly reduced the incidence of AngII-induced AAAs (cilnidipine: 38 %, Vehicle: 88 %; P < 0.05). Elastica van Gieson staining demonstrated degeneration of elastic lamina by AngII was suppressed by cilnidipine administration. Immunohistochemical staining of CD68 revealed that cilnidipine administration attenuated accumulation of CD68 positive macrophage by AngII. In addition, cilnidipine reduced oxidative stress by AngII in 8-hydroxy-2’-deoxyguanosine and 4-Hydroxy-2-nonenal staining. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice by its anti-inflammation and anti-oxidative stress effect.

Shear Stress and Angiotensin II in the Development and Localization of Abdominal Aortic Aneurysms

2009 ◽  
Author(s):  
Michelle Consolini ◽  
Tiziano Passerini ◽  
Marina Piccinelli ◽  
Brandon Fornwalt ◽  
Nick G. Willett ◽  
...  
Keyword(s):  
Shear Stress ◽  
Angiotensin Ii ◽  
Wall Shear Stress ◽  
Lower Extremities ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Infrarenal Aorta ◽  
Abdominal Aortic ◽  
Suprarenal Aorta ◽  
Wall Shear

Abdominal aortic aneurysms (AAAs) develop in the infrarenal aorta of humans and in the suprarenal aorta of apoE−/− mice infused with angiotensin II (AngII). Oscillatory wall shear stress in the infrarenal human abdominal aorta is driven by the flow to the gastric arteries, the lumbar curvature and the capacitance of the lower extremities [1]. Two of these factors, the lumbar curvature and the capacitance of the lower extremities, are significantly different in mice than in humans. Therefore, we hypothesized that the differences in localization of AAAs between species is explained by differences in the pattern of wall shear stress via the shear-regulated modulation of inflammatory pathways involving AngII.

Regional Anesthesia for Endovascular Treatment of Abdominal Aortic Aneurysms

1997 ◽  
Vol 4 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Petter Aadahl ◽  
Jan Lundbom ◽  
Staal Hatlinghus ◽  
Hans O. Myhre
Keyword(s):  
Blood Pressure ◽  
Endovascular Treatment ◽  
Arterial Blood Pressure ◽  
Regional Anesthesia ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Arterial Blood ◽  
Open Operation ◽  
Early Results ◽  
Abdominal Aortic

Purpose: To investigate the feasibility of regional anesthesia for endovascular repair of abdominal aortic aneurysms (AAAs). Methods: Since February 1995, 21 patients (17 men and 4 women; median age 67 years, range 49 to 80) have been treated with endovascular technique for true infrarenal AAA using Mialhe Stentor bifurcated grafts. A single dose of spinal anesthesia combined with epidural anesthesia was used in all procedures. Electrocardiography and arterial blood pressure were monitored. Results: No cases of emboli, hematoma, or graft migration were seen, and there were no reoperations or conversions to open operation. Arterial blood pressure was stable at a satisfactory level from induction of anesthesia throughout the procedure, and there was no period of clinically significant hypotension during any implantation. One patient died on the second postoperative day from cardiac and renal insufficiency. Three endoleaks were observed during the procedure; one healed spontaneously within 5 weeks, and the other two were repaired by endovascular techniques after 1 and 4 months, respectively. During follow-up, one patient died at 6 months from pancreatic carcinoma. Conclusions: The application of regional anesthesia is feasible for endovascular treatment of AAA. The arterial blood pressure remained stable throughout the procedure, and all patients, with two exceptions, were mobilized on the first day and placed on a regular diet. Based on these early results, it appears that regional anesthesia is feasible, effective, and safe for endovascular AAA repair.

Mechanisms of Abdominal Aortic Aneurysm Formation in Persons With Traumatic Amputation of a Lower Extremity

2011 ◽  
Author(s):  
Alexander V. Smolensky ◽  
Stephanie Clement-Guinaudeau ◽  
Michael K. Larche ◽  
John N. Oshinski ◽  
W. Robert Taylor
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Lower Extremity ◽  
Aortic Aneurysms ◽  
Arterial Blood Flow ◽  
Infrarenal Aorta ◽  
Traumatic Amputation ◽  
Arterial Blood ◽  
Abdominal Aortic ◽  
Retrograde Blood Flow

Abdominal aortic aneurysms (AAA) are a major cause of morbidity and mortality in the US. The incidence of AAA in older Americans approaches 30%. The most common place of AAA is infrarenal abdominal aorta where oscillatory shear stress (OSS) is present. OSS is known to initiate an inflammatory response in the endothelium. It is known that there is up to a 5-fold increase in the occurrence of AAA in individuals with traumatic amputation of a lower extremity. This increased AAA occurrence is unrelated to co-morbid conditions. We recruited 3 healthy volunteers who underwent infrarenal abdominal aortic Magnetic Resonance angiography and phase contrast imaging. These measurements were done at base line and with acute arterial blood flow occlusion to lower extremity with a blood pressure cuff to mimic amputation. The collected data was used to calculate systolic forward and diastolic retrograde blood flow and wall shear stress during cardiac cycle. Our results suggest that mimicking amputation produces a nearly doubling of retrograde blood flow with ∼50% increase of negative WSS. These changes are more pronounced on the contralateral to the “amputation” side. We conclude that lower extremity traumatic amputations may lead to augmentation of OSS in infrarenal aorta causing AAA development.

scholarly journals Vinpocetine protects against the development of experimental abdominal aortic aneurysms

2020 ◽  
Vol 134 (22) ◽  
pp. 2959-2976
Author(s):  
Chongyang Zhang ◽  
Chia George Hsu ◽  
Amy Mohan ◽  
Hangchuan Shi ◽  
Dongmei Li ◽  
...  
Keyword(s):  
Cerebrovascular Disorders ◽  
Degenerative Disease ◽  
Aortic Aneurysms ◽  
Infrarenal Aorta ◽  
Post Intervention ◽  
Aged Population ◽  
Elastin Degradation ◽  
Abdominal Aortic ◽  
Aneurysmal Dilation

Abstract Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.

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

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

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.

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