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

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.

Download Full-text

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

Journal of the American Heart Association ◽

10.1161/jaha.120.018536 ◽

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.

Download Full-text

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

PLoS ONE ◽

10.1371/journal.pone.0049642 ◽

2012 ◽

Vol 7 (12) ◽

pp. e49642 ◽

Cited By ~ 36

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

Download Full-text

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

Circulation ◽

10.1161/circ.118.suppl_18.s_369 ◽

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).

Download Full-text

Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling

Science China Life Sciences ◽

10.1007/s11427-015-0277-8 ◽

2016 ◽

Vol 59 (9) ◽

pp. 940-949 ◽

Cited By ~ 11

Author(s):

Fang Wang ◽

Houzao Chen ◽

Yunfei Yan ◽

Yue Liu ◽

Shuyang Zhang ◽

...

Keyword(s):

Angiotensin Ii ◽

P38 Mapk ◽

Abdominal Aortic Aneurysms ◽

Mapk Signaling ◽

Aortic Aneurysms ◽

Abdominal Aortic

Download Full-text

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

Circulation ◽

10.1161/circulationaha.108.844589 ◽

2010 ◽

Vol 121 (11) ◽

pp. 1338-1346 ◽

Cited By ~ 32

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

Download Full-text

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽

10.1161/circ.116.suppl_16.ii_108-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Miao Wang ◽

Jane Stubbe ◽

Eric Lee ◽

Wenliang Song ◽

Emanuela Ricciotti ◽

...

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Aortic Aneurysms ◽

Ang Ii ◽

Abdominal Aortic ◽

Density Lipoprotein Receptor ◽

The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

Download Full-text

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_180-d ◽

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.

Download Full-text