Simvastatin Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-Knockout Mice

Abstract

Objective-Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE Ϫ/Ϫ ) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation. Methods and Results-ApoEϪ/Ϫ mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells. Key Words: angiotensin II Ⅲ abdominal aortic aneurysm Ⅲ statin Ⅲ ERK inhibition Ⅲ angiogenesis A bdominal aortic aneurysm (AAA) is a potentially lifethreatening degenerative vascular disease that affects 6% to 9% of men over the age of 65 years, claiming more than 15 000 lives annually. 1 Currently, surgical repair is the only effective method of AAA treatment. 2 Studies of the pathophysiology of AAA have demonstrated that human aneurysmal tissues are characterized by (1) chronic inflammation of the aortic wall with the accumulation of macrophages and MCP-1 secretion 3 ; (2) progressive degradation of extracellular matrix including elastin and collagen 4 ; (3) increased activity of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9 5 ; (4) reendothelialization of the dilated luminal surface of the vessel wall and pronounced neovascularization of the media and adventitia. 6,7 Several animal models of AAA have been developed in the mouse, including injury of the aortic wall with calcium chloride 8 or elastase. 9 Infusion of AngII via subcutaneous osmotic minipumps in ApoE Ϫ/Ϫ mice has also been shown to result in reproducible formation of suprarenal AAAs, which exhibit many characteristics of the human disease including secretion of MCP-1, 5 macrophage infiltration, secretion of MMPs, disruption of the media, rupture of the elastic layer, and neovascularization. 10 This is consistent with the finding that AngII not only plays a role in the control of cardiovascular and renal homeostasis but also affects vascular endothelial cell function, macrophage activation, 11 and the contraction, migration, and proliferation of vascular smooth muscle cells. 12 This model supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA and is thus an important model for the study of mechanisms of AAA formation. Conclusions-TheseThe mitogen-activated protein (MAP) kinase family, including ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK...

Regulatory T Cells Prevent Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice

“…24 In the present study, NF-κB and ERK1/2 activation was significantly attenuated in Tregs-treated HASMCs, suggesting that the effect of Tregs on HASMCs was via downregulating angiotensin II-mediated NF-κB and ERK1/2 activation.…”

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…It has also been reported that a DPP-4I inhibited toll-like receptor 4-mediated extracellular signalregulated kinase (ERK) activation and ERK-dependent MMP expression in monocytes 31,38) . ERK activation is known to be involved in Ang -induced AAA formation 39) . Therefore, a DPP-4I may suppress MMP-9 expression through IL-1 expression and ERK activation in AAA formation.…”

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

“…[5,17] Placebo, STAT3 inhibitor S3I-201 (5 mg/kg, i.p., every other day, Selleckchem) or TLR4 antagonist Eritoran (0.3 mg/kg, i.v., every other day, Eisai Inc.) were given for 28 days. S3I-201 inhibits STAT3 phosphorylation with an IC 50 = 86 µM.…”

“…Western blot analysis was performed as previously described. [17] The Tyr705 specific pSTAT3 and total STAT3 antibodies were obtained from Cell Signaling Technology; the TLR4 and GAPDH antibodies were obtained from Santa Cruz Biotechnology. The protein bands were visualized using chemiluminescent substrates (Pierce).…”

“…[17,31,32] To determine whether AngII stimulation of MMP secretion was dependent on pSTAT3, the effect of S3I-201 on MMP2 and MMP9 activity in suprarenal aortas of AngII-treated ApoE -/-mice was measured. S3I-201 treatment significantly down-regulated MMP9 activity (9.50±0.65 vs. 1.73±0.31 fold in AngII and AngII+S3I-201 treated mice, respectively), and MMP2 activity (5.10±0.28 vs. 1.73±0.14 fold, n=4, p<0.01) ( Fig.…”