scholarly journals Vasohibin-2 Aggravates Development of Ascending Aortic Aneurysms But Not Abdominal Aortic Aneurysms Nor Atherosclerosis in ApoE Deficient Mice

2020 ◽  
Author(s):  
Nozomu Otaka ◽  
Haruhito A Uchida ◽  
Michihiro Okuyama ◽  
Yoshiko Hada ◽  
Yasuhiro Onishi ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Abdominal Aortic Aneurysms ◽  
Ascending Aorta ◽  
Aortic Aneurysms ◽  
Vascular Pathology ◽  
Osmotic Pumps ◽  
Abdominal Aortic ◽  
Deficient Mice

Abstract Background Vasohibin-2 (VASH2) has been isolated as a homologue of vasohibin-1 (VASH1) that promote angiogenesis counteracting with VASH1. Chronic angiotensin II (AngII) infusion promotes both ascending and abdominal aortic aneurysms (AAs) in mice. The present study aimed to investigate whether exogenous VASH2 influenced AngII-induced vascular pathology in apolipoprotein E deficient (ApoE  -/-) mice. Methods Male, ApoE  -/- mice (9 to 14 weeks old) were injected with Ad LacZ or Ad VASH2. After a week, saline or AngII (1,000 ng/kg/min) was infused into the mice subcutaneously via mini-osmotic pumps for 3 weeks. Consequently, all these mice were divided into 4 groups: saline + LacZ (n=5), saline + VASH2 (n=5), AngII + LacZ (n=18), and AngII + VASH2 (n=17). Results Exogenous VASH2 had no significant effect on ex vivo maximal diameters of abdominal aortas (AngII + LacZ; 1.67±0.17 mm, AngII + VASH2; 1.52±0.16 mm, n.s.) or elastin fragmentation and accumulation of inflammatory cells. Conversely, exogenous VASH2 significantly increased intima areas of aortic arches (AngII + LacZ; 16.6±0.27 mm 2, AngII + VASH2; 18.6±0.64 mm 2, p=0.006). VASH2 effect of AngII-induced ascending AAs was associated with increased cleaved caspase-3 abundance. AngII-induced atherosclerosis was not altered by VASH2. Conclusion The present study demonstrated that augmented VASH2 expression had no effect of AngII-induced abdominal AAs or atherosclerosis, while increasing dilation in the ascending aorta.

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 404: Cilostazol Attenuated Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E--Deficient Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ryoko Umebayashi ◽  
Haruhito A Uchida ◽  
Hirofumi Makino
Keyword(s):  
Angiotensin Ii ◽  
Apolipoprotein E ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Gelatin Zymography ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Maximal Diameter ◽  
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. Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet aggregation and vasodilatory effects, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in several experimental studies. The purpose of this study was to evaluate whether cilostazol influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either AngII (1,000 ng/kg/min, n = 16 -18) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. AngII equivalently increased systolic blood pressure, irrespective of cilostazol adminstration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. Cilostazol did not affect ex vivo measurement of maximal diameter of abdominal aorta (0.88 ± 0.04 mm vs 0.88 ± 0.03 mm, n.s.) in saline infused-mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas but cilostazol administration attenuated (1.94 ± 0.16 mm vs 1.53 ± 0.17 mm, P < 0.05). In addition, gelatin zymography demonstrated that cilostazol diminished AngII-induced increase in aortic MMP-2 activity (P < 0.05). Conclusion: Cilostazol attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

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 919: Suppression of Abdominal Aortic Aneurysms in the Angiotensin II-infused ApoE Deficient Mice by Treatment with Chymase Inhibitor

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nao Inoue ◽  
Michiko Muramatsu ◽  
Denan Jin ◽  
Shinji Takai ◽  
Tetsuya Hayashi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Treated Group ◽  
Aortic Aneurysms ◽  
Aortic Diameter ◽  
Vehicle Group ◽  
Control Group ◽  
Abdominal Aortic ◽  
Chymase Inhibitor ◽  
Deficient Mice

Chymase promotes not only angiotensin II production but also matrix metalloproteinase (MMP)-9 activation, which have a critical role on development of abdominal aortic aneurysms (AAAs). The purpose of this study is to examine the effects of chymase inhibitor, NK3201, on the MMP-9 activity and development of AAA in the angiotensin II-induced apolipoprotein E (apoE)-deficient mice. Method: Angiotensin II (1000ng/kg/min) (vehicle group) or saline (control group) were infused into 16-week-old male apoE-deficient mice for 4 weeks. To examine the effect of chymase inhibition for AAA, we administered NK3201 (30mg/kg/day) to angiotensin II-infused group (NK3201-treated group) for the same period. At the end of angiotensin II infusion, we measured the diameters of suprarenal and infrarenal aorta. AAA severities were scored using the suprarenal aortic diameter/infrarenal aortic diameter ratio and presence of thrombus formation, i.e. under 2.0 was 0, from 2.0 to 2.5 was 1, from 2.5 to 3.0 was 2, over 3.0 was 3, and presence of thrombus was 4. We also determined the chymase and MMP-9 activities using total aorta. Results: The scores that reflected the progression and severity of AAA were increased in vehicle group compared with control group ( 2.35±0.30 vs. 0.27±0.12, p<0.01). This progression was inhibited in NK3201-treated group compared with vehicle group (1.13±0.35, p<0.05 vs. vehicle group). Chymase activity was significantly increased in vehicle group compared with control group. MMP-9 activity was also increased in vehicle group, however it was decreased significantly in NK3201-treated group.Discussion: We demonstrated that chymase inhibition could reduce AAA progression through inhibition of MMP-9 in angiotensin II-induced apoE-deficient mice. Chymase inhibitor might be a novel strategy for preventing AAAs.

Abstract 86: Intercellular Adhesion Molecule 1 Deficiency Attenuated Angiotensin II--Induced Abdominal Aortic Aneurysms in Apolipoprotein E--Deficient Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Haruhito A Uchida ◽  
Ryoko Umebayashi ◽  
Yuki Kakio ◽  
Kenichi Shikata ◽  
Hirofumi Makino
Keyword(s):  
Body Weight ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Normal Diet ◽  
Aortic Aneurysms ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Abdominal Aortic ◽  
Deficient Mice ◽  
Mini Pump

Objective: Chronic infusion of angiotensin II (AngII) augments the development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Several studies have suggested that intercellular adhesion molecule 1 (ICAM-1) expression increases in association with AAA formation. The aim of the study was to define whether ICAM deficiency influenced AngII-induced AAA formation. Methods and Results: Apolipoprotein E deficient (apoE -/-) mice were cross-bred with ICAM-1 deficient mice. Male apoE -/- mice fed a normal diet and infused subcutaneously with saline or AngII (1,000 ng/kg/min) via osmotic mini pump for 1 week. AngII infusion increased aortic ICAM-1 protein. Male apoE -/- mice that were either ICAM-1 +/+ or -/- were fed a normal diet and infused subcutaneously with AngII (1,000 ng/kg/min) via osmotic mini pump for 4 weeks. Total ICAM-1 deficiency had no significant effect on body weight, total cholesterol concentrations, or systolic blood pressures prior to and during AngII infusion. AngII induced expansion of ex vivo maximal diameters of abdominal aortas was attenuated significantly in ICAM-1 deficient mice (ICAM-1 +/+, 1.78 ± 0.20 mm; ICAM-1 -/-, 1.07 ± 0.03 mm, P < 0.0001). ICAM-1 deficiency also reduced significantly the incidence of AngII-induced AAAs (ICAM-1 +/+, 76%; ICAM-1 -/-, 13%, P < 0.0001). Furthermore, bone-marrow transplantation was performed to develop chimeric mice that were ICAM-1 +/+ or -/- in donor cells and ICAM-1 +/+ or -/- in recipient cells. ICAM-1 deficiency in either donor or recipient cells had no effect on body weight, total cholesterol concentrations, or systolic blood pressure. Recipient ICAM-1 deficiency significantly attenuated the incidence of AngII-induced AAA formation (ICAM-1 +/+, 67%; ICAM-1 -/-, 19%, P = 0.0008). Furthermore, lack of ICAM-1 reduced AngII-induced aortic MMP-2 activation (P < 0.05). Conclusion: ICAM-1 deficiency attenuated AngII-induced AAAs in male apoE -/- mice.

scholarly journals Assessment of Elastase-Induced Murine Abdominal Aortic Aneurysms: Comparison of Ultrasound Imaging withIn SituVideo Microscopy

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Junya Azuma ◽  
Lars Maegdefessel ◽  
Toshiro Kitagawa ◽  
Ronald L. Dalman ◽  
Michael V. McConnell ◽  
...  
Keyword(s):  
High Frequency ◽  
Ex Vivo ◽  
Linear Regression Analysis ◽  
Intraclass Correlation ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Control Group ◽  
High Frequency Ultrasound ◽  
Luminal Diameter ◽  
Abdominal Aortic

Aims. The aim of this study was to definitively assess the validity of noninvasive high-frequency ultrasound (US) measurements of aortic luminal diameter (ALD) in a murine model of elastase-induced abdominal aortic aneurysm in comparison with in situ video microscopy (VM).Methods. C57BL/6 mice underwent transient perfusion of the aorta with either elastase (n=20: Elastase group) or saline (n=10: Sham). Unoperated mice (n=10) were also studied.Results. ALD measurements by US had excellent linear correlation and absolute agreement with that by VM in both Control (unoperated or sham-operated mice) and elastase groups (r=0.96, intraclass correlation coefficient(ICC)=0.88andr=0.93,ICC=0.92, resp.). Bland-Altman analysis of US compared with VM measurements in both groups indicated good agreement, however US measurements were slightly but significantly higher than VM measurements in the control group (mean bias 0.039 mm,P<.05). Linear regression analysis revealed excellent correlation between US and VM measurements in both groups. (R2=0.91in Control group,R2=0.85in elastase group.) The reliability of US measurements was also confirmed by ex vivo histological measurements.Conclusions.High-frequency US provides reliable ALD measurements in developing murine abdominal aortic aneurysms.

ABDOMINAL AORTIC ANEURYSMS: A NOVEL EX VIVO CELL CULTURE METHOD TO ANALYSE INFLAMMATORY AND ANGIOGENIC PATHWAYS

2004 ◽  
Vol 13 (3) ◽  
pp. 18
Author(s):  
Alexandra Kovalic ◽  
Claudia Monaco ◽  
Roger M Greenhalgh ◽  
Ian J Franklin ◽  
Ewa M Paleolog
Keyword(s):  
Cell Culture ◽  
Ex Vivo ◽  
Culture Method ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic
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