Abstract Aims Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. Methods and results Two independent case–control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. Conclusions ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

The mitochondrial enzyme acetaldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease (CVD), cancer and Alzheimer's, among other diseases. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models in which AKI was induced by either the contrast agent Iohexol or renal ischemia/reperfusion, knockout and activation/overexpression of ALDH2 was associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation and eliminated reactive oxygen species (ROS). In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2 mediated renoprotection. In mice with Iohexol induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to Iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. Our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.

BACKGROUND: Clinical studies show that the most common single-point mutation in humans, ALDH2 (aldehyde dehydrogenase 2) rs671 mutation, is a risk factor for the development and poor prognosis of atherosclerotic cardiovascular diseases, but the underlying mechanism remains unclear. Apoptotic cells are phagocytosed and eliminated by macrophage efferocytosis during atherosclerosis, and enhancement of arterial macrophage efferocytosis reduces atherosclerosis development. METHODS: Plaque areas, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated in APOE −/− mice with bone marrow transplanted from APOE − /− ALDH2 − /− and APOE − /− mice. RNA-seq, proteomics, and immunoprecipitation experiments were used to screen and validate signaling pathways affected by ALDH2. Efferocytosis and protein levels were verified in human macrophages from wild-type and rs671 mutation populations. RESULTS: We found that transplanting bone marrow from APOE − /− ALDH2 − /− to APOE − /− mice significantly increased atherosclerosis plaques compared with transplanting bone marrow from APOE − /− to APOE − /− mice. In addition to defective efferocytosis in plaques of APOE − /− mice bone marrow transplanted from APOE − /− ALDH2 − /− mice in vivo, macrophages from ALDH2 − /− mice also showed significantly impaired efferocytotic activity in vitro. Subsequent RNA-seq, proteomics, and immunoprecipitation experiments showed that wild-type ALDH2 directly interacted with Rac2 and attenuated its degradation due to decreasing the K48-linked polyubiquitination of lysine 123 in Rac2, whereas the rs671 mutant markedly destabilized Rac2. Furthermore, Rac2 played a more crucial role than other Rho GTPases in the internalization process in which Rac2 was up-regulated, activated, and clustered into dots. Overexpression of wild-type ALDH2 in ALDH2 − /− macrophages, rather than the rs671 mutant, rescued Rac2 degradation and defective efferocytosis. More importantly, ALDH2 rs671 in human macrophages dampened the apoptotic cells induced upregulation of Rac2 and subsequent efferocytosis. CONCLUSIONS: Our study has uncovered a pivotal role of the ALDH2-Rac2 axis in mediating efferocytosis during atherosclerosis, highlighting a potential therapeutic strategy in cardiovascular diseases, especially for ALDH2 rs671 mutation carriers.

Background: Patients with acute heart failure (AHF) who require continuous renal replacement therapy (CRRT) have a high risk of in-hospital mortality. It is clinically important to screen high-risk patients using a model or scoring system. This study aimed to develop and validate a simple-to-use nomogram consisting of independent prognostic variables for the prediction of in-hospital mortality in patients with AHF undergoing CRRT.Methods: We collected clinical data for 121 patients with a diagnosis of AHF who underwent CRRT in an AHF unit between September 2011 and August 2020 and from 105 patients in the medical information mart for intensive care III (MIMIC-III) database. The nomogram model was created using a visual processing logistic regression model and verified using the standard method.Results: Patient age, days after admission, lactic acid level, blood glucose concentration, and diastolic blood pressure were the significant prognostic factors in the logistic regression analyses and were included in our model (named D-GLAD) as predictors. The resulting model containing the above-mentioned five factors had good discrimination ability in both the training group (C-index, 0.829) and the validation group (C-index, 0.740). The calibration and clinical effectiveness showed the nomogram to be accurate for the prediction of in-hospital mortality in both the training and validation cohort when compared with other models. The in-hospital mortality rates in the low-risk, moderate-risk, and high-risk groups were 14.46, 40.74, and 71.91%, respectively.Conclusion: The nomogram allowed the optimal prediction of in-hospital mortality in adults with AHF undergoing CRRT. Using this simple-to-use model, the in-hospital mortality risk can be determined for an individual patient and could be useful for the early identification of high-risk patients. An online version of the D-GLAD model can be accessed at https://ahfcrrt-d-glad.shinyapps.io/DynNomapp/.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT0751838.

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