No Effect of Hypercholesterolemia on Elastase-Induced Experimental Abdominal Aortic Aneurysm Progression.
No Effect of Hypercholesterolemia on Elastase-Induced Experimental Abdominal Aortic Aneurysm Progression.
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DOI：
10.3390/biom11101434
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发表时间：
2021-09-30
期刊：
影响因子：
5.5
通讯作者：
Dalman RL
中科院分区：
文献类型：
--
作者：
Ikezoe T;Shoji T;Guo J;Shen F;Lu HS;Daugherty A;Nunokawa M;Kubota H;Miyata M;Xu B;Dalman RL
目的：流行病学研究将高脂血症与腹主动脉瘤（AAA）风险增加联系起来。然而，降脂药物他汀类药物对临床和实验性AAA的患病率和进展的影响在不同的报告之间存在差异，这引起了对高脂血症与AAA疾病相关性的争议。本研究调查了高胆固醇血症对弹性蛋白酶诱导的小鼠实验性AAAs的影响。方法：采用自发性（靶向删除载脂蛋白E）和诱导性小鼠高胆固醇血症模型。在雄性野生型（WT）C57 BL/6 J小鼠中，通过腹膜内注射编码功能获得性前蛋白转化酶枯草杆菌蛋白酶/kexin 9型突变（PCSK 9）的腺相关病毒（AAV），随后给予高脂饮食（HFD）（PCSK 9 +HFD）2周，诱导高胆固醇血症。作为PCSK 9 +HFD小鼠的正常胆固醇血症对照，WT小鼠用PCSK 9 AAV感染并喂食正常食物，或单独注射磷酸盐缓冲盐水并喂食HFD食物。通过主动脉内输注猪胰弹性蛋白酶在所有小鼠中诱导AAA，并通过超声和组织病理学进行评估。结果如下：在自发性高胆固醇血症和正常胆固醇血症雄性小鼠中，弹性蛋白酶输注后第3天至第14天，主动脉直径以恒定速率扩大。在所有小鼠中形成AAA，定义为直径比基线测量值增加超过50%。AAA进展在有或没有自发性高脂血症的雄性小鼠中更明显。自发性高胆固醇血症雄性小鼠（弹性蛋白评分为3.5，平滑肌评分为4.0）和正常胆固醇血症雄性小鼠（均为4.0）的弹性蛋白降解和平滑肌细胞耗竭程度相似。两组之间的主动脉壁巨噬细胞积聚也相当。在自发性高胆固醇血症和正常胆固醇血症雄性小鼠之间，未观察到CD 4+或CD 8 + T细胞、B细胞或壁血管生成的主动脉蓄积存在差异。同样，在雌性小鼠中未观察到自发性高胆固醇血症对特征性囊性组织病理学的影响。在验证性实验中，诱导的高胆固醇血症对AAA进展和组织病理学也没有明显影响。结论：本研究表明，在自发性和诱导性高胆固醇血症小鼠模型中，高胆固醇血症对弹性蛋白酶诱导的实验性AAA进展均无可识别的影响。这些结果进一步增加了围绕他汀类药物治疗临床AAA疾病疗效的争议的不确定性。
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.
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DOI：
10.1161/atvbaha.116.307613
发表时间：
2016-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Lu H;Howatt DA;Balakrishnan A;Graham MJ;Mullick AE;Daugherty A
通讯作者：
Daugherty A
影响因子：
5.3
作者：
Bobryshev, YV;Lord, RSA
通讯作者：
Lord, RSA
DOI：
10.1111/j.1749-6632.1999.tb07789.x
发表时间：
1999-01-01
期刊：
THE METABOLIC SYNDROME X
影响因子：
--
作者：
Daugherty, A;Cassis, L
通讯作者：
Cassis, L
影响因子：
8.3
作者：
Niederhoffer, N;LartaudIdjouadiene, I;Atkinson, J
通讯作者：
Atkinson, J
影响因子：
3.4
作者：
Golledge, Jonathan;Cullen, Bradford;Rush, Catherine
通讯作者：
Rush, Catherine