The effects of neutrophil elastase on obesity-related vascular damage
Embargo Date
2025-02-13
OA Version
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Abstract
INTRODUCTION: As obesity rates continue to rise around the world, it is essential to understand the pathological consequences that may follow as a result. This need is further enhanced by the position of cardiovascular disease (CVD) as one of the leading factors contributing to American deaths. This study investigates the complex connections between diet, age, and NE. Along with their individual and compounding impacts on vascular damage of the aorta.
Obesity promotes many disease states, many of which increase the chances of cardiovascular events. One such consequence of obesity is the establishment of chronic low-grade inflammation of the cardiovascular tissues, among many other anatomical structures that are also affected. This inflammatory response that arises from obesity has been linked with morphological changes such as fibrosis and calcification. Age has also been observed to promote the degradation and stiffening of many components of the aorta, as cells either become senescent or damaged throughout life.
The main interest of this study is to observe the impact of neutrophil elastase (NE) has on the aorta as a result of age and obesogenic diets. Markers for inflammation and damage to the aorta were evaluated.
OBJECTIVES: Obesity and age have impacts on the progression of CVD and other comorbidities. This study will investigate the key factors that increase inflammatory response and other pathological changes in the aorta under high-fat high-fructose diet (HFHFD) and aging conditions. In addition, we will explore the impact of NE on HFHFD- and aging-induced inflammation and pathological changes in the aorta.
METHODS: Mice were separated into different dietary groups, and further separated into 2 age groups consisting of old mice and young mice. The old mice were designated with either a normal chow diet (NCD) or a HFHFD. These old mice were kept on their respective diets for 1.0 year. The young mice were split into groups and were fed a NCD, a HFHFD, and a high-fat diet (HFD) for 6 months. Within both age group, there were also groups of mice that were neutrophil elastase knockout (NEKO). After the respective periods in which the mice were fed with the same diets as WT mice were. At the end of the feeding experiments, the mice were euthanized and aortic tissue samples were collected.
By using WT and NEKO mice, various pathological patterns have been observed to commonly occur as a result of obesity and age. The deposition of calcium along the walls of the aorta were visualized with an Alizarin Red stain. Similarly, collagen deposition, which can signify the presence of fibrosis, was detected with a Picrosirius Red (PSR) stain and with anti-collagen antibody immunohistochemical staining. Through its autofluorescence at a wavelength of 480 nm, elastin and elastin fragmentation in the aorta was also examined. Immunofluorescence (IF) was used for various immune cells and NE to determine their degree of infiltration within the aortic walls of the mice.
RESULTS: The wild-type (WT) mice fed on HFHFDs had significantly more damage than any of the other dietary groups in both the young and old mice groups. The WT-HFHFD old mice had higher degrees of elastin fragmentation, immune cell infiltration, calcification, and fibrosis. Although these pathological changes were also consistent with the young WT-HFHFD mice, this group was not as severely affected as the WT-HFHFD old mice.
When given the same HFHFD to the NEKO mice, there was a significant decrease in vascular damage. For the most part, the states of the aortas collected from the NEKO-HFHFD mice were more similar to those of the WT-NCD mice than the WT-HFHFD mice. Since the NEKO-HFHFD mice had less pathological changes, this suggests that deletion of NE leads to significant decrease in vascular damage caused by aging and obesity.
CONCLUSION: Despite the beneficial functions of neutrophils and NE when released, this protease plays an essential role in the development of several morphologic and pathologic changes that are associated with age and obesity. The absence of NE provided a protective effect as it significantly alleviated many of the pathological changes that contribute to the development of life-threatening cardiovascular disease (CVD).
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Attribution 4.0 International