Involvement of HIF-1/Trf/Fe2+ signaling pathway in the Pathogenesis of Stanford Type A Aortic Dissection

Background Stanford type A aortic dissection (TAAD), as one of the most lethal cardiovascular disease, may be mediated by cellular ferroptosis, which exacerbates structural modification and dysfunction of endothelial and smooth muscle cells. Hypoxia inducible factor-1 (HIF-1), as a transcription factor has shown participate in the course of ferroptosis. However, the mechanism involved has not been uncovered clearly. Methods We collected clinical basic information and image data of TAAD patients received surgical operation for aortic replacement and non- TAAD patients who suffered from other surgeries including cardiac transplantation or aortic valve replacement. Then aortic tissues being replaced from each group was analyzed through RNA-sequencing to reveal underlying molecular mechanism participated in TAAD. Then, according to genes and signaling pathway selected, qRT-PCR and western blot were further implemented to verify the expression quantity of proteins. Results Baseline characteristics including age, gender, and other variables were non-differential between two groups. Computed tomography angiography (CTA) showed that linear low-density structure referring to tearing intima was floated in the full-course of aortic lumen which was separated into the true lumen and the false lumen. Disordered cells arrangement and fractured fibrous tissue were displayed in the H&E staining and Masson staining. RNA-seq found that more than 5000 differential genes were expressed in TAAD patients if |log ₂ FC|≥1 and P value ≤ 0.5. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEEG) analysis revealed that genes related cellular ferroptosis and HIF-1 signaling pathway were expressed differentially and significantly during the development of TAAD. Moreover, the proteins of SLC7A11 and GPX4 which related ferroptosis were up-regulated, as well as the HIF-1 protein and its downstream protein of transferrin receptor 1(Trf1), which were in line with the results of RT-PCR. The amount of Fe ²⁺ was greater in aorta from TAAD patients than that from non-TAAD patients. Conclusion Cellular feroptosis plays a vital role during the development of TAAD, and the HIF-1/Trf/Fe ²⁺ pathway was involved in the regulation of cellular ferroptosis.