Xiqiang Wang

Background: Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque‐resident mechanisms through which the diabetic milieu promotes macrophage lipid‐oxidative injury are not fully understood. Methods: We used apolipoprotein E‐deficient ( ApoE ^−/− ) mice with Mex‐3 RNA‐binding family member A (MEX3A) deficiency and primary bone marrow‐derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid‐peroxidation injury. Results: MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4‐hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9‐mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation‐qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid‐peroxidation injury in Mex3a ‐knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re‐expression. Ferrostatin‐1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions: Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4‐linked ferroptosis‐associated mechanism in plaque macrophages. Key points: MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid‐peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin‐1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.

To date, our understanding of the global aortic aneurysm (AA) burden distribution is very limited. To assess a full view of global AA burden distribution and attributable risk factors from 1990 to 2017. We extracted data of AA deaths, disability-adjusted life years (DALYs), and their corresponding age-standardized rates (ASRs), in general and by age/sex from the 2017 Global Burden of Disease (GBD) study. The current AA burden distribution in 2017 and its changing trend from 1990 to 2017 were separately showed. The spatial divergence was discussed from four levels: global, five social-demographic index regions, 21 GBD regions, and 195 countries and territories. We also estimated the risk factors attributable to AA related deaths. Globally, the AA deaths were 167,249 with an age-standardized death rate (ASDR) of 2.19/100,000 persons in 2017, among which the elderly and the males accounted for the majority. Although reductions in ASRs were observed in developed areas, AA remained an important health issue in those relatively underdeveloped areas and might be much more important in the near future. AA may increasingly affect the elderly and the female population. Similar patterns of AA DALYs burden were noted during the study period. AA burden attributable to high blood pressure and smoking decreased globally and there were many heterogeneities in their distribution. AA maintained an incremental public health issue worldwide. The change pattern of AA burden was heterogeneous across locations, ages, and sexes and it is paramount to improve resource allocation for more effective and targeted prevention strategies. Also, prevention of tobacco consumption and blood pressure control should be emphasized.