Perivascular adipose tissue-derived nitric oxide compensates endothelial dysfunction in aged pre-atherosclerotic apolipoprotein E-deficient rats
Background and aims: Atherosclerosis is a major contributor to global mortality and is accompanied by vascular inflammation and endothelial dysfunction. Perivascular adipose tissue (PVAT) is an established regulator of vascular function with emerging implications in atherosclerosis. We investigated the modulation of aortic relaxation by PVAT in aged rats with apolipoprotein E deficiency (ApoE-/-) fed a high-fat diet as a model of early atherosclerosis.
Methods and results: ApoE-/- rats (N = 7) and wild-type Sprague-Dawley controls (ApoE+/+, N = 8) received high-fat diet for 51 weeks. Hyperlipidemia was confirmed in ApoE-/- rats by elevated plasma cholesterol (p < 0.001) and triglyceride (p = 0.025) levels. Early atherosclerosis was supported by increased intima/media thickness ratio (p < 0.01) and ED1-positive macrophage influx in ApoE-/- aortic intima (p < 0.001). Inflammation in ApoE-/- PVAT was characteristic by an increased [18F]FDG uptake (p < 0.01), ED1-positive macrophage influx (p = 0.0003), mRNA expression levels of CD68 (p < 0.001) and IL-1β (p < 0.01), and upregulated iNOS protein (p = 0.011). The mRNAs of MCP-1, IL-6 and adiponectin remained unchanged in PVAT. Aortic PVAT volume measured with micro-PET/CT was increased in ApoE-/- rats (p < 0.01). Maximal endothelium-dependent relaxation (EDR) to acetylcholine in ApoE-/- aortic rings without PVAT was severely impaired (p = 0.012) compared with controls, while ApoE-/- aortic rings with PVAT showed higher EDR than controls. All EDR responses were blocked by L-NMMA and the expression of eNOS mRNA was increased in ApoE-/- PVAT (p = 0.035).
Conclusion: Using a rat ApoE-/- model of early atherosclerosis, we capture a novel mechanism by which inflammatory PVAT compensates severe endothelial dysfunction by contributing NO upon cholinergic stimulation.
A longitudinal 18 F-fluorodeoxyglucose ( 18 F-FDG) and 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography/computed tomography (PET/CT) study in apolipoprotein E (ApoE) knockout rats fed with a Western diet
Background: Inflammation and vascular calcification are risk factors for cardiovascular disease, but their relationship is still under investigation. This longitudinal in vivo study aimed to monitor inflammation and calcification during the formation of atherosclerotic plaques in apolipoprotein E knockout (ApoE-/-) rats by 18F-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT).
Methods: In the ApoE group, male ApoE-/- rats were fed a high-fat Western diet from 13 weeks of age, and in the normal group, male SD rats of the same age were fed a normal diet. A longitudinal PET/CT study using 18F-FDG and 18F-NaF was performed at 12, 27, and 46 weeks of age. T1-weighted magnetic resonance imaging (MRI) was used as an atlas template, and the uptake of the tracers in the cardiovascular system was analyzed based on atlas 3D geometry volumes-of-interest (VOIs). After the PET/CT study, pathological and immunohistochemical examinations were performed on the corresponding lesions.
Results: The body weight and plasma cholesterol levels of the ApoE-/- rats increased with time, and at each time point, significantly higher body weight and plasma cholesterol levels were observed in the ApoE-/- rats than in the normal rats. PET/CT showed that in ApoE-/- rats, the uptake of 18F-FDG was found in the aortic arch, while the uptake of 18F-NaF was found in pulmonary arteries. The uptake of the two tracers in the ApoE group increased with time. Extensive early stage of atherosclerotic plaques, with high expression of CD68 and alizarin red, were observed in pulmonary arteries. However, only a thickened intima with very high expression of hypoxia-inducible factor-1 alpha (HIF-1α) was seen in the aortic arch.
Conclusions: In ApoE-/- rats fed a high-fat Western diet, early atherosclerotic lesions developed in the pulmonary arteries; however, 18F-FDG failed to accumulate in these lesions but to accumulate in the aortic arch with only neointimal hyperplasia and significantly high expression of hypoxia.
Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics.
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-Apoe tm1sage (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.
Rat apolipoprotein E (Apo-E) ELISA |
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Apolipoprotein E-deficient rats develop atherosclerotic plaques in partially ligated carotid arteries.
BACKGROUND
The goal of this study was to establish an apolipoprotein E-deficient (ApoE(-/-)) rat model.
METHODS
The ApoE(-/-) rat was created by TALEN-mediated gene targeting in the genetic background of Sprague Dawley rat. Six-to eight-week-old male rats were used in the experiments (n = 10 in each group).
RESULTS
After fed with high-cholesterol diet (HCD) for 12 weeks, the ApoE(-/-) rats displayed typical dyslipidemia. In contrast, HCD failed to induce hypercholesterolemia in wild-type rats. However, there was no obvious atherosclerotic lesion in oil red O-stained en face aortas and the aortic root sections in both genetic types of rats. Interestingly, partial ligation caused the formation of plaques consist of lipid and macrophages in carotid arteries from ApoE(-/-) rats, but induced the neointimal hyperplasia in wild-type rats. Additionally, we found that HCD slightly increased the expression of adhesion molecules, while partial ligation dramatically upregulated these molecules.
CONCLUSIONS
The ApoE(-/-) rat is a novel model for dyslipidemia and could also be used in the research of atherosclerosis.