Development of Accelerated Coronary Atherosclerosis Model Using Low Density Lipoprotein Receptor Knock-Out Swine with Balloon Injury.
Development of Accelerated Coronary Atherosclerosis Model Using Low Density Lipoprotein Receptor Knock-Out Swine with Balloon Injury.
复制标题
DOI：
10.1371/journal.pone.0163055
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Daida H
中科院分区：
文献类型：
--
作者：
Ogita M;Miyauchi K;Onishi A;Tsuboi S;Wada H;Konishi H;Naito R;Dohi T;Kasai T;Kojima Y;Schwartz RS;Daida H
几种动物模型促进了对动脉粥样硬化的评估和病理学理解，但尚无明确的冠状动脉粥样硬化动物模型。因此，我们开发了患有高胆固醇血症的低密度脂蛋白受体敲除（LDLR-KO）猪，这种模型在球囊损伤后迅速发展为冠状动脉粥样硬化。我们从培养的猪胎儿成纤维细胞中删除了 LDLR 外显子区域，并克隆了 LDLR 敲除 (LDLR-KO) 胚胎，将胎儿成纤维细胞核显微注射到去核卵母细胞中。 12 头 LDLR-KO 猪饲喂 2.0% 胆固醇和 20% 脂肪的饮食。基线血清 LDL 胆固醇水平为 510.0±86.1 mg/dL。在 46 个冠状动脉节段中造成球囊损伤，并在 2、4、8 和 12 周后进行尸检。检查冠状动脉切片以评估病变进展。我们发现泡沫细胞和炎症细胞在球囊损伤后四个星期开始出现脂质积累。与两周相比，第 4 周和第 8 周动物的巨噬细胞与斑块面积的平均比率显着更高（8.79% ± 5.98% 和 17.00% ± 10.38% vs. 1.14% ± 1.88%，P < 0.0001）。第 12 周时，该比率下降至第 2 周水平（4.00% ± 4.56%，相对于基线，P = 0.66）。晚期冠状动脉粥样硬化病变在第 8 周时含有脂质池，并在第 12 周时开始含有纤维成分。我们使用球囊损伤的 LDLR KO 猪开发了快速冠状动脉粥样硬化模型。该模型可能有助于药物或设备的临床前评估，也可能有助于研究斑块进展的机制。
Several animal models have facilitated the evaluation and pathological understanding of atherosclerosis, but a definitive animal model of coronary atherosclerosis is not available. We therefore developed low density lipoprotein receptor knockout (LDLR-KO) pigs with hypercholesterolemia, a model which rapidly developed coronary atherosclerosis following balloon injury. We deleted LDLR exon regions from cultured porcine fetal fibroblasts and cloned LDLR knockout (LDLR-KO) embryos microinjecting fetal fibroblast nuclei into enucleated oocytes. Twelve LDLR-KO pigs were fed a 2.0% cholesterol and 20% fat diet. Baseline serum LDL cholesterol level was 510.0±86.1 mg/dL. Balloon injury was created in 46 coronary segments and necropsy were obtained 2, 4, 8 and 12 weeks later. Coronary artery sections were reviewed to evaluate lesion progression. We found lipid accumulation with foam cells and inflammatory cells beginning four weeks after balloon injury. The mean ratio of macrophages to plaque area was significantly higher in the four- weeks and eight-week animals compared with those at 2-weeks (8.79% ± 5.98% and 17.00% ± 10.38% vs. 1.14% ± 1.88%, P < 0.0001). At 12 weeks the ratio decreased toward the level at 2 week level (4.00% ± 4.56%, P = 0.66 vs. baseline). Advanced coronary atherosclerotic lesions contained lipid pools at eight-weeks with fibrous components beginning at 12 weeks. We developed a model of rapid coronary atherosclerosis using LDLR KO pigs with balloon injury. This model may be useful for preclinical evaluation of medication or devices, and may also help investigate mechanisms of plaque progression.
登录
查看更多内容
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
37.8
作者：
Bentzon, Jacob F.;Sondergaard, Claus S.;Falk, Erling
通讯作者：
Falk, Erling
DOI：
10.1161/01.atv.0000247243.48542.9d
发表时间：
2006-12-01
影响因子：
8.7
作者：
Bentzon, Jacob F.;Weile, Charlotte;Falk, Erling
通讯作者：
Falk, Erling
影响因子：
3.7
作者：
Ozawa M;Himaki T;Ookutsu S;Mizobe Y;Ogawa J;Miyoshi K;Yabuki A;Fan J;Yoshida M
通讯作者：
Yoshida M
影响因子：
5.3
作者：
REITMAN, JS;MAHLEY, RW;FRY, DL
通讯作者：
FRY, DL