Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor Antagonist–Inhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice

Abstract

We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis. We divided IL-1Ra+/−/apolipoprotein-E (apoE)−/− and IL-1Ra+/+/apoE−/− mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra+/+/apoE+/+ mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups. At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra+/−/apoE−/− mice was significantly greater than that in the IL-1Ra+/+/apoE−/− mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra+/−/apoE−/− mice than in the IL-1Ra+/+/apoE−/− mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra+/−/apoE−/− mice were higher than in the IL-1Ra+/+/apoE−/− mice (P <0.01). Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE−/− mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE−/− mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression.

Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis

“…The effects of rilonacept on CRP level and endothelial function are evaluated in a randomized clinical trial [63]. Also, treatment with recombinant IL-1ra has been shown to be a successful antiatherosclerotic therapy in mice [64].…”

A preclinical ultrasound method for the assessment of vascular disease progression in murine models

“…22 A number of in vivo imaging studies have been carried out on mice demonstrating a correlation between high-frequency ultrasound and standard ex vivo methods. [23][24][25][26][27] However, many of the current preclinical ultrasoundbased methods in use (for example: assessment of morphology, circumferential strain, dimensions and wall stiffness) suffer from drawbacks including high user-dependency of the method with regard to acquisition mode, measurement (e.g. diameter), image angle (long or short axis) and analysis methods applied.…”

MicroRNA-217 attenuates intima–media complex thickness of ascending aorta measured by ultrasound bio-microscopy and inhibits inflammation and lipid metabolism in atherosclerotic models of ApoE−/− mice

“…Ultrasound bio-microscopy enables evaluation of plaque size and stenosis in vivo, noninvasively, and in real-time [ 17 , 23 – 25 ], which has been widely used to detect spontaneously formed plaques in the brachiocephalic [ 26 , 27 ], thoracic arteries [ 24 , 28 ], and the ascending aorta [ 23 ]. In this study, such technique is used to monitor the development of plaque of atherosclerosis and such technique will give the longitudinal study possible.…”

“…Apolipoprotein E (ApoE) −/− mice (6–8 weeks old) were ordered from Peking Vital River Laboratory Animal Ltd. (Beijing, China) and fed with the high-fat diet (HFD, 20% fat, 20% sugar, and 1.25% cholesterol) for 3 months as previously reported to induce atherosclerosis [ 17 ]. The ApoE −/− mice were further classified into three groups at random: 10 for the AS group, 10 for the miR-217 group, and 10 for the miRNA nonspecific control (NS-miR group).…”