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. 2022 Jul 26;146(21):1591–1609. doi: 10.1161/CIRCULATIONAHA.121.057623

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© 2022 The Authors.

Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

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Figure 8. — Supplementation with the ACO2 downstream metabolite αKG protects against AAA formation. A, Schematic protocol: saline- or AngII-infused ApoE^−/−/Nr1d1^flox/flox and ApoE^−/−/Nr1d1^ΔSMC mice were intraperitoneally injected with vehicle or DM-αKG (100 mg/kg/d) for 28 days. B, Representative images of the macroscopic features of AAA formation in indicated groups. C, The incidence of AAA formation in indicated groups (n=30 per group). Data were analyzed by a Fisher exact test. *P<0.05; **P<0.01; ***P<0.001. D, Quantification of the maximal diameter of suprarenal abdominal aortas measured using a Digital Vernier Caliper (n=22–30 per group). Data were analyzed by 2-way ANOVA followed by the Bonferroni post hoc test. **P<0.01; ***P<0.001. E, Quantification of total aortic weight/BW (n=22–30 per group). Data were analyzed by 2-way ANOVA followed by the Bonferroni post hoc test. ***P<0.001. F, Representative images of suprarenal abdominal aortas visualized by MUI using the B mode in indicated groups. G, Quantification of the maximal diameter of suprarenal abdominal aortas measured by MUI using the B mode in indicated groups (n=22–30 per group). Data were analyzed by 2-way ANOVA followed by the Bonferroni post hoc test. **P<0.01; ***P<0.001. Data are expressed as mean ± SEM. H, Schematic representation of the molecular mechanisms. Under a pathological state during AAA development, upregulation of NR1D1 represses the nuclear transcription of Aco2 in VSMCs with recruitment of the NCoR1-HDAC3 corepressor complex. Consequently, reduced ACO2 expression and activity suppress the TCA cycle, disrupt mitochondrial homeostasis, and subsequently trigger VSMCs apoptosis, eventually resulting in the formation of AAA. Supplementation with αKG, a downstream metabolite of ACO2, alleviates mitochondrial dysfunction and restricts AAA formation. AAA indicates abdominal aortic aneurysm; ACO2, aconitase-2; αKG, α-ketoglutarate; AngII, angiotensin II; DM-αKG, dimethyl α-ketoglutarate; HDAC3, histone deacetylase 3; MUI, micro-ultrasound imaging; NCoR1, nuclear receptor corepressor 1; NR1D1, nuclear receptor subfamily 1 group D member 1; NS, nonsignificant; SMC, smooth muscle cell; TCA, tricarboxylic acid; and VSMCs, vascular smooth muscle cells.