Metabolomic Profiling of Angiotensin-II-Induced Abdominal Aortic Aneurysm in Ldlr−/− Mice Points to Alteration of Nitric Oxide, Lipid, and Energy Metabolisms

Abstract

Aneurysm is the second-most common disease affecting the aorta worldwide after atherosclerosis. While several clinical metabolomic studies have been reported, no study has reported deep metabolomic phenotyping in experimental animal models of aortic aneurysm. We performed a targeted metabolomics study on the blood and aortas of an experimental mice model of aortic aneurysm generated by high-cholesterol diet and angiotensin II in Ldlr−/− mice. The mice model showed a significant increase in media/lumen ratio and wall area, which is associated with lipid deposition within the adventitia, describing a hypertrophic remodeling with an aneurysm profile of the abdominal aorta. Altered aortas showed increased collagen remodeling, disruption of lipid metabolism, decreased glucose, nitric oxide and lysine metabolisms, and increased polyamines and asymmetric dimethylarginine (ADMA) production. In blood, a major hyperlipidemia was observed with decreased concentrations of glutamine, glycine, taurine, and carnitine, and increased concentrations of the branched amino acids (BCAA). The BCAA/glycine and BCAA/glutamine ratios discriminated with very good sensitivity and specificity between aneurysmatic and non-aneurysmatic mice. To conclude, our results reveal that experimental induction of aortic aneurysms causes a profound alteration in the metabolic profile in aortas and blood, mainly centered on an alteration of NO, lipid, and energetic metabolisms.

Gasdermin D Deficiency in Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis

“…[ 12 ] High concentrations of putrescine have been detected in cancer and inflammatory bowel diseases. [ 13 , 14 ] Metabolomic phenotyping of experimental animal models of AAA has shown that putrescine is upregulated in the blood and aortas of Ang II‐induced mice; [ 15 ] however, the role of putrescine in aortic aneurysms remains unclear.…”

Glutamine Protects against Mouse Abdominal Aortic Aneurysm through Modulating VSMC Apoptosis and M1 Macrophage Activation

“…[35]. Additionally, the level of glutamine was reported to be decreased in AngII-treated group [36], therefore, we conducted this study to validate whether supplementation of glutamine protected mice from AAA, since AngII-induced mouse AAA model is widely used in laboratory. Although some side effects of chronic glutamine supplementation have been discussed [37], it is still widely used as an anti-fatigue amino acid in sport field [38].…”

Transcriptomic analysis identifies the shared diagnostic biomarkers and immune relationship between Atherosclerosis and abdominal aortic aneurysm based on fatty acid metabolism gene set

“…Previous studies have shown that altered lipid metabolism contributes to the formation of atherosclerotic plaques and the weakening of the aortic wall, leading to the development of AS ( Zhu et al, 2016 ; Guo et al, 2019 ). The induction of AAA through experimentation leads to a significant change in the metabolic profile of both the aortas and blood, primarily focusing on the modification of lipid metabolism ( Guo et al, 2020 ; Chao de la Barca et al, 2022 ). In addition, SIRT4 in mitochondria regulates fatty acid oxidation and its deficiency promotes AS through NF-κB pathway activation ( Chang et al, 2023 ).…”

“…The experimental induction of AAA leads to significant changes in the metabolic composition of both aortas and blood. These changes are primarily focused on the disruption of nitric oxide production, lipid metabolism, and energy-related metabolic pathways ( Guo et al, 2020 ; Chao de la Barca et al, 2022 ). Elevated lipoprotein levels have been found to be an independent indicator of increased risk of disease in patients with AAA ( Kubota et al, 2018 ).…”