No Effect of Hypercholesterolemia on Elastase-Induced Experimental Abdominal Aortic Aneurysm Progression.

Toru Ikezoe,Baohui Xu,Masao Nunokawa,Masaaki Miyata,Hiroshi Kubota,Alan Daugherty,Jia Guo,Hong S Lu,Fanru Shen,Takahiro Shoji,Ronald L Dalman

doi:10.3390/biom11101434

Abstract

Objective: Epidemiological studies link hyperlipidemia with increased risk for abdominal aortic aneurysms (AAAs). However, the influence of lipid-lowering drugs statins on prevalence and progression of clinical and experimental AAAs varies between reports, engendering controversy on the association of hyperlipidemia with AAA disease. This study investigated the impact of hypercholesterolemia on elastase-induced experimental AAAs in mice. Methods: Both spontaneous (targeted deletion of apolipoprotein E) and induced mouse hypercholesterolemia models were employed. In male wild type (WT) C57BL/6J mice, hypercholesterolemia was induced via intraperitoneal injection of an adeno-associated virus (AAV) encoding a gain-of-function proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) followed by the administration of a high-fat diet (HFD) (PCSK9+HFD) for two weeks. As normocholesterolemic controls for PCSK9+HFD mice, WT mice were infected with PCSK9 AAV and fed normal chow, or injected with phosphate-buffered saline alone and fed HFD chow. AAAs were induced in all mice by intra-aortic infusion of porcine pancreatic elastase and assessed by ultrasonography and histopathology. Results: In spontaneous hyper- and normo-cholesterolemic male mice, the aortic diameter enlarged at a constant rate from day 3 through day 14 following elastase infusion. AAAs, defined as a more than 50% diameter increase over baseline measurements, formed in all mice. AAA progression was more pronounced in male mice, with or without spontaneous hyperlipidemia. The extent of elastin degradation and smooth muscle cell depletion were similar in spontaneous hyper- (score 3.5 for elastin and 4.0 for smooth muscle) and normo- (both scores 4.0) cholesterolemic male mice. Aortic mural macrophage accumulation was also equivalent between the two groups. No differences were observed in aortic accumulation of CD4+ or CD8+ T cells, B cells, or mural angiogenesis between male spontaneous hyper- and normocholesterolemic mice. Similarly, no influence of spontaneous hypercholesterolemia on characteristic aneurysmal histopathology was noted in female mice. In confirmatory experiments, induced hypercholesterolemia also exerted no appreciable effect on AAA progression and histopathologies. Conclusion: This study demonstrated no recognizable impact of hypercholesterolemia on elastase-induced experimental AAA progression in both spontaneous and induced hypercholesterolemia mouse models. These results add further uncertainty to the controversy surrounding the efficacy of statin therapy in clinical AAA disease.

Highlights

Abdominal aortic aneurysms (AAAs) are a life-threatening consequence of aging.Development of abdominal aortic aneurysms (AAAs) disease is predicated on both inherited and acquired predispositions.Epidemiological studies associate hypercholesterolemia with modest AAA disease risk relative to those posed by cigarette smoking (2.61–12.13, depending on intensity and duration), male sex (5.71) and advancing age (1.67–28.37) [1,2]
Female mice experienced less aortic diameter enlargement than strainmatched male mice following porcine pancreatic elastase (PPE) infusion, regardless of ApoE status (Figure 2E,F). These data indicate that spontaneous hypercholesteremia due to ApoE deficiency had no impact on sex-dependent differences in experimental AAA progression. These results indicate that spontaneous hypercholesterolemia in mice deficient for ApoE exerts minimal influence on development and progression of PPE-induced experimental AAAs
(D,G) indicated no significance difference between two groups. These results indicate that spontaneous hypercholesterolemia exerted no measurable results indicate that spontaneous hypercholesterolemia exerted no measurable effectThese on characteristic experimental

Summary

Introduction

Abdominal aortic aneurysms (AAAs) are a life-threatening consequence of aging.Development of AAA disease is predicated on both inherited and acquired predispositions (www.cdc.gov/heartdisease/aortic_aneurysm.htm, accessed on 20 September 2021).Epidemiological studies associate hypercholesterolemia with modest AAA disease risk (odds ratio 1.31–1.44) relative to those posed by cigarette smoking (2.61–12.13, depending on intensity and duration), male sex (5.71) and advancing age (1.67–28.37) [1,2]. Abdominal aortic aneurysms (AAAs) are a life-threatening consequence of aging. Development of AAA disease is predicated on both inherited and acquired predispositions (www.cdc.gov/heartdisease/aortic_aneurysm.htm, accessed on 20 September 2021). Epidemiological studies associate hypercholesterolemia with modest AAA disease risk (odds ratio 1.31–1.44) relative to those posed by cigarette smoking (2.61–12.13, depending on intensity and duration), male sex (5.71) and advancing age (1.67–28.37) [1,2]. Elevated lipid variant genetic risk scores have been associated with AAA disease (odds ratio 1.40–1.47) [3]. Interventional trials of serum lipid-lowering pharmaceutical strategies to limit progression of clinical and experimental AAAs using β-hydroxy β-methylglutaryl-CoA reductase inhibitors, aka statins, have produced inconsistent results [4,5,6,7,8,9,10,11,12,13].

Methods

Findings

Discussion

Conclusion