Occlusal disharmony accelerates the initiation of atherosclerosis in apoE knockout rats

Ekuni, Daisuke; Yoneda, Toshiki; Endo, Yoshikatsu; Kasuyama, Kenta; Irie, Koichiro; Mizutani, Shinsuke; Azuma, Tetsuji; Tomofuji, Takaaki; Morita, Manabu

doi:10.1186/1476-511x-13-144

Cited by 17 publications

(16 citation statements)

References 50 publications

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“…Different models of APOE-deficiency have been generated by various gene editing strategies in rats. These Apoe −/− rats display a range of atherosclerosis phenotypes, ranging from no detectable lesions, to very early signs of lipid deposition and atherosclerosis ( 55 , 56 , 153 , 154 ), at least as compared with Apoe −/− mice, to more advanced lesions ( 57 ). Thus, one Apoe −/− rat model exhibits an atherosclerosis phenotype similar to that of the Apoe −/− mice described above but lesion progression appears to be generally slower than that in the mouse.…”

Section: Animal Models Of Hypertriglyceridemia and Their Susceptibilimentioning

confidence: 99%

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and because they are enriched in cholesterol relative to triglycerides, which promotes pro-atherogenic effects in lesional cells. Other mechanistic studies show that hepatic receptors (LDLR and LRP1) and APOE are critical for RLP clearance. Thus, studies in animal models have provided additional mechanistic insight and generally agree with the hypothesis that RLPs derived from TRLs are highly atherogenic whereas hypertriglyceridemia due to accumulation of very large TRLs in plasma is not markedly atherogenic in the absence of TRL lipolysis products.

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Section: Animal Models Of Hypertriglyceridemia and Their Susceptibilimentioning

confidence: 99%

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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“…Today, the introduction of the nuclease techniques, such as Zinc Finger (ZF) 26 , Transcription Activator-Like Effector Nuclease (TALEN) 27 and recently Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) 28 have enabled easy gene deletion in species other than mice. In 2011, scientists at Sigma’s Advanced Genetic Engineering (SAGE) Labs created ApoE gene knockout ( Apoe −/− ) rats by the use of ZF technology 29 . Only limited data on Apoe −/− rats exist 29 , 30 .…”

Section: Introductionmentioning

confidence: 99%

“…In 2011, scientists at Sigma’s Advanced Genetic Engineering (SAGE) Labs created ApoE gene knockout ( Apoe −/− ) rats by the use of ZF technology 29 . Only limited data on Apoe −/− rats exist 29 , 30 . In two previous studies describing Apoe −/− rat models 29 , 30 , very early fatty streak lesions were demonstrated.…”

Section: Introductionmentioning

confidence: 99%

“…Only limited data on Apoe −/− rats exist 29 , 30 . In two previous studies describing Apoe −/− rat models 29 , 30 , very early fatty streak lesions were demonstrated. However, in one of the studies, in which the rats were fed a high fat diet for only 12 weeks, no vascular lesions were detected unless the carotid artery was partially ligated 30 .…”

Section: Introductionmentioning

confidence: 99%

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Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Rune

Rolin

Lykkesfeldt

et al. 2018

Sci Rep

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In the apolipoprotein E–deficient mouse, the gut microbiota has an impact on the development of atherosclerosis, but whether such correlations are also present in rats requires investigation. Therefore, we studied female SD-Apoetm1sage (Apoe−/−) rats fed either a Western diet or a low-fat control diet with or without gluten, which is known to promote gut microbiota changes, until 20 weeks of age. We hypothesized that the manifestation of atherosclerosis would be more severe in Apoe−/− rats fed the Western high-fat diet, as compared with rats fed the low-fat diet, and that atherosclerosis would be accelerated by gluten. Both Western diet-feeding and gluten resulted in significant changes in gut microbiota, but the microbiota impact of gluten was transient. Compared with Apoe−/− rats fed a low-fat diet, Western diet-fed Apoe−/− rats were heavier and became glucose intolerant with increased levels of oxidative stress. They developed early fatty streak lesions in their aortic sinus, while there was no evidence of atherosclerosis in the thoracic aorta. No conclusions could be made on the impact of gluten on atherosclerosis. Although Western diet-fed Apoe−/− rats exhibited a more human-like LDL dominated blood lipid profile, signs of obesity, type 2 diabetes and cardiovascular disease were modest.

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“…Nowadays, with the application of novel gene editing techniques (TALEN and CRISPR/Cas system) knockout rats can be produced quickly and efficiently. There were already reports about ApoE knockout rats [ 16 – 17 ] . The plasma cholesterol levels of ApoE KO rats were 1.5-fold higher than WT controls, but significantly lower than ApoE KO mice, which are consistent with the present data.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a rat model with diet-induced coronary atherosclerosis

et al. 2017

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Coronary atherosclerotic disease is a serious disease in humans, but no suitable animal model is available currently for further studies. We used apolipoprotein E gene knockout (ApoE KO) rats to induce hypercholesterolemia through a special high cholesterol/bile salt diet (Paigen diet), then analyzed aortic and coronary atherosclerosis lesions and the myocardial injury in order to establish a novel small animal model of coronary atherosclerosis. Plasma cholesterol of ApoE KO rats increased 7.6-fold compared with wild-type rats after 8 weeks on the Paigen diet. After 10 to 12 weeks of subsisting on the Paigen diet, ApoE KO rats developed mild aortic atherosclerosis with severe coronary atherosclerosis. Hematoxilyn and eosin staining showed that 11 out of 12 ApoE KO male rats had right coronary artery atherosclerosis, 7 of them were>70% occluded. Oil Red O (Lipid Stain), Mac2 immuno-staining and Masson’s trichrome staining demonstrated substantial amounts of lipid, macrophages and collagen fibers in coronary atherosclerosis plaques. In addition, ApoE KO male rats had severe myocardial focal lesions with cholesterol ester as the main component in the lesions. In conclusion, ApoE KO rats developed severe hypercholesterolemia, coronary atherosclerosis and myocardial cholesterol ester deposition after subsisting on the Paigen diet and can be used as a novel animal model for studies on cholesterol metabolism and coronary atherosclerotic disease.

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Occlusal disharmony accelerates the initiation of atherosclerosis in apoE knockout rats

Cited by 17 publications

References 50 publications

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Establishment of a rat model with diet-induced coronary atherosclerosis

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