Dataset Information

Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis.

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common animal models for NASH and accompanying liver fibrosis, but there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the pathology of NASH patients with atherosclerosis. Rabbits can be a promising candidate for assessing NASH and atherosclerosis because lipoprotein metabolism is more similar to humans compared with rodents. To develop the NASH model using rabbits, we treated the Japanese White rabbit with a newly developed high-fat high-cholesterol diet (HFHCD) containing palm oil 7.5%, cholesterol 0.5%, and ferrous citrate 0.5% for 16 weeks. HFHCD-fed rabbits exhibited NASH at 8 weeks after commencing the treatment and developed advanced fibrosis by the 14th week of treatment. In addition to hypercholesterolemia, atherosclerotic lesion developed in the aorta after 8 weeks. Therefore, this rabbit NASH model might contribute to exploring the concurrent treatment options for human NASH and atherosclerosis.

SUBMITTER: Hayashi M

PROVIDER: S-EPMC9953079 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis.

Hayashi Momoko M Kuwabara Yoshibumi Y Ito Kuniji K Hojo Yoshiaki Y Arai Fumiaki F Kamijima Kazuki K Takeiri Masakazu M Wang Xiaojing X Diao Pan P Nakayama Jun J Tanaka Naoki N

Biomedicines 20230127 2

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common animal models for NASH and accompanying liver fibrosis, but there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the ...[more]

PMID: 36830921

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Project description:BackgroundAortic atherosclerosis increases the risk of embolic events under extracorporeal circulation (ECC). To evaluate the hemodynamic impact of ECC on atheromatous plaques, an atherosclerosis animal model, which is also eligible for ECC, is required.MethodsTwenty-nine New Zealand White rabbits received a pro-atherosclerotic diet (group diet, n = 10), a pro-atherosclerotic diet and additional intraaortic balloon insufflation injury (group BI, n = 9), or served as controls (n = 10). After 3 or 6 months, aortic explants were analyzed by (immuno-)histology and RT-PCR.ResultsBlood serum analyses revealed increased cholesterol-levels in groups diet and BI compared to controls (3 months: p = 0.03 each, 6 months: p < 0.0001 each). Aortic inflammatory infiltration was significantly enhanced in groups diet (CD3 at 3 months: p < 0.0001, 6 months: p = 0.02; CD68 at 3 months: p = 0.01) and BI (CD3 at 3 months: p < 0.0001, 6 months: p = 0.03; CD68 at 3 months: p = 0.04, 6 months: p = 0.02). Increased intima hyperplasia occurred in both groups (p < 0.0001 each). Macroscopic analyses after 3 and 6 months showed ubiquitous lumen-narrowing aortic plaques. Calcification of the intima and media was increased in groups diet (intima: p < 0.0001 at 3 and 6 months; media at 3 months: p < 0.0001, 6 months: p = 0.01) and BI (intima: p < 0.0001 at 3 and 6 months; media at 3 months: p < 0.0001, 6 months: p = 0.02). Extensive lipid accumulation was found in the intima in both treatment groups (p < 0.0001 each).ConclusionsA rabbit model with high aortic calcific plaque burden-diet-induced with no implicit need of an additional intimal injury by an intraaortic balloon insufflation due to comparable outcome-exhibiting multiple pathophysiological aspects of human atherosclerosis has been designed and thoroughly characterized. It is suitable for use in future studies on the interaction between atherosclerotic plaques and the arterial blood flow under ECC.

Project description:The macrophage-rich core of advanced human atheroma has been demonstrated to be hypoxic, which may have implications in plaque stability. The goal of this study was to determine the feasibility of the hypoxia PET imaging agent 64Cu-ATSM to detect hypoxia in a rabbit model of atherosclerosis imaged on a simultaneous PET/MR scanner, using MR for both attenuation correction and depiction of lesion location.MethodsNew Zealand White rabbits fed a Western diet for 4-6 wk underwent endothelial denudation of the right femoral artery by air desiccation to induce an atherosclerotic-like lesion and underwent a sham operation on the left femoral artery. Four and 8 wk after injury, a 0- to 60-min dynamic whole-body PET/MR examination was performed after injection of approximately 111 MBq of 64Cu-ATSM. After 24 h, a 0- to 75-min dynamic PET/MR examination after injection of approximately 111 MBq of 18F-FDG was performed. The rabbits were euthanized, and the injured femoral artery (IF) and sham-operated femoral artery (SF) were collected for immunohistochemistry assessment of hypoxic macrophages (hypoxia marker pimonidazole, macrophage marker RAM-11, and hypoxia-inducible factor-1 α subunit [HIF-1α]). Regions of interest of IF, SF, and background muscle (BM) were drawn on fused PET/MR images, and IF-to-BM and SF-to-BM SUV ratios were compared using the Student t test.ResultsElevated uptake of 64Cu-ATSM was found in the rabbits' IF compared with the SF. 64Cu-ATSM imaging demonstrated IF-to-SF SUVmean ratios (±SD) of 1.75 ± 0.21 and 2.30 ± 0.26 at 4 and 8 wk after injury, respectively. 18F-FDG imaging demonstrated IF-to-SF SUVmean ratios of 1.84 ± 0.12 at 8 wk after injury. IF-to-BM SUVmean ratios were significantly higher (P < 0.001) than SF-to-BM SUVmean ratios both 4 and 8 wk after injury for 64Cu-ATSM and 8 wk after injury for 18F-FDG (P < 0.05). Pimonidazole immunohistochemistry at 8 wk colocalized to RAM-11 and HIF-1α.ConclusionThe results show that hypoxia is present in this rabbit model of atherosclerosis and suggest that 64Cu-ATSM PET/MR is a potentially promising method for the detection of hypoxic and potentially vulnerable atherosclerotic plaque in human subjects.

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Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis.

Publications

Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis.

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