BACKGROUND: Aortic aneurysm/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the E3 ubiquitin ligase March2 (membrane-associated RING [really interesting new gene] finger protein 2) to the cause of AAD remains elusive. METHODS: Integrated single-cell RNA sequencing analysis was conducted in human AAD tissues. Based on the screening results, we generated a mouse line of smooth muscle cell–specific March2 knockout. β-Aminopropionitrile monofumarate was used to establish AAD. Cleavage under targets and tagmentation and cleavage under targets and tagmentation–quantitative polymerase chain reaction were performed to identify possible target genes for histone H3K18 lactylation. RESULTS: March2 expression was downregulated in aorta from patients with AAD or β-aminopropionitrile monofumarate–induced AAD mice. β-Aminopropionitrile monofumarate–induced AAD was significantly accentuated in March2 global (March2 ^–/– ) and vascular smooth muscle cell–specific deletion (March2 ^fl/fl ; Tagln ^Cre ) mice, whereas the AAD pathology was rescued by rAAV9-SM22α (smooth muscle 22α)-March2 (recombinant adeno-associated virus serotype 9 expressing Flag-tagged March2 under SM22α promoter). March2 interacted with PKM2 (pyruvate kinase M2) to promote K33-linked polyubiquitination. Deficiency of March2 lessened PKM2 dimer-to-tetramer conversion in AAD and overtly exacerbated AAD-induced histone H3K18 lactylation in vascular smooth muscle cells by fostering glucose metabolism reprogramming, thereby promoting p53-driven apoptotic transcriptional response—a hallmark of AAD pathogenesis. TEPP-46 (tetraethyl pyrophosphate), a PKM2-specific activator, pronouncedly alleviated March2 deficiency–deteriorated AAD pathology. CONCLUSIONS: Our findings demonstrated that March2 is a novel endogenous defender that prevents AAD by inhibiting vascular smooth muscle cell apoptosis, suggesting that March2 represents a potential therapeutic target for AAD.

Purpose: To explore the predictive value of ACEF scores for identifying the risk of cardiovascular disease (CVD) in the general population. Methods: A total of 8613 participants without a history of CVD were enrolled in the follow-up. The endpoint was CVD incidence, defined as stroke or coronary heart disease (CHD) diagnosed during the follow-up period. Cox regression analyses were used to calculate hazard ratios (HRs) with respect to the age, creatinine, and ejection fraction (ACEF) scores and CVD. A Kaplan–Meier curve was used to analyze the probability of CVD in different quartiles of ACEF. Restricted cubic spline was used to further explore whether the relationship between ACEF and CVD was linear. Finally, we assessed the discriminatory ability of ACEF for CVD using C-statistics, net reclassification index, and integrated discrimination improvement (IDI). Results: During a median follow-up period of 4.66 years, 388 participants were diagnosed with CVD. The Kaplan–Meier curve showed that ACEF was associated with CVD, and participants with high ACEF scores were significantly more likely to be diagnosed with CVD compared to participants with low ACEF scores in the general population. In the multivariate Cox regression analysis, the adjusted HRs for four quartiles of ACEF were as follows: the first quartile was used as a reference; the second quartile: HR = 2.33; the third quartile: HR = 4.81; the fourth quartile: HR = 8.00. Moreover, after adding ACEF to the original risk prediction model, we observed that new models had higher C-statistic values of CVD than the traditional model. Furthermore, the results of both NRI and IDI were positive, indicating that ACEF enhanced the prediction of CVD. Conclusions: Our study showed that the ACEF score was associated with CVD in the general population in northeastern China. Furthermore, ACEF could be a new tool for identifying patients at high risk of primary CVD in the general population.

BACKGROUND: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. The mitochondrial AAA ⁺ ATPase ATAD3A (ATPase family AAA domain–containing protein 3A), enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear. METHODS: AAD was induced in wild-type, ATAD3A knock-in, and vascular smooth muscle cell (VSMC)–specific knockdown (sh-ATAD3A) mice by 3-week β-aminopropionitrile monofumarate intake or 28-day AngII (angiotensin II) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. Vascular smooth muscle cells were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca ^{2 +} imaging. ATAD3A–DLST (dihydrolipoamide S -succinyltransferase) interaction was examined by coimmunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat. RESULTS: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in β-aminopropionitrile monofumarate–treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated β-aminopropionitrile monofumarate–induced and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca ^{2 +} influx, and suppressed the FDXR (ferredoxin reductase)/FDX1 (ferredoxin 1)/LIAS (lipoic acid synthetase) lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using tetrathiomolybdate or Devimistat attenuated disease severity in vivo. CONCLUSIONS: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca ^{2 +} influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.