Identification of endoplasmic reticulum stress-associated lncRNAs influencing inflammation and VSMC function in abdominal aortic aneurysm.

Abstract

Endoplasmic reticulum (ER) stress plays a critical role in the abdominal aortic aneurysm (AAA), a life-threatening disease characterized by inflammation, destructive remodeling, and vascular smooth muscle cells (VSMCs) dysfunction. The current therapy relies on surgical repair, but no effective pharmacological strategies are available to limit aneurysm progression. Long non-coding RNAs (lncRNAs) are essential factors in health and disease; however, their specific contribution to AAA development and its relationship with ER stress remain unexplored. Here, we have performed a whole-genome transcriptomic analysis characterizing the expression profile of lncRNAs in AAA. RNA sequencing was carried out in abdominal aorta from patients with AAA and healthy donors. We identified 6576 differentially expressed (DE)-mRNAs and 1283 DE-lncRNAs. Interestingly, bioinformatic analysis revealed a set of 368 DE-lncRNAs related to ER stress. The differential expression of the most induced lncRNAs (IL-21-AS1, ITPKB-IT, PCED1B-AS1, TCL-6, LINC00494, LINC00582, LINC00626, LINC00861, and LINC00892) was validated in a large cohort of patients with AAA. The ability of these selected lncRNAs to discriminate patients with AAA from healthy subjects was established by receiveroperating characteristic curves and logistic regression analysis. In human aortic VSMC and Jurkat T-cells, tunicamycin-induced ER stress triggered the expression of IL21-AS1, LINC00626, LINC00494, LINC00892, PCED1B-AS1, ITPKB-IT, and TCL-6, while tauroursodeoxycholic acid counteracted these effects. Finally, an integrated analysis of mRNA-lncRNA co-expression revealed the correlation between the selected lncRNAs and the DE-mRNAs involved in immune response and muscle contraction. Therefore, these DE-lncRNAs potentially implicated in the ER stress response, a pathological process in AAA, could be considered as potential therapeutic target to handle AAA.