DKK1/SMDT1 participate in Ang II-induced mitochondrial injury of human smooth muscle cells in an abdominal aortic aneurysm cell model

Abdominal aortic aneurysm (AAA) is a lethal vascular disease, in which Apoptosis and inflammation participate. However, the regulatory factors associated with aortic status remain unclear; therefore, a deeper understanding of the cell types and signaling pathways involved in the pathological process of AAAs is key to the development of medical treatments. The aim of the present study was to explore the role of dickkopf-1 (DKK1) in angiotensin (Ang) II-stimulated human smooth muscle cells (HSMCs), and to clarify the potential downstream targets and related pathological mechanisms of DKK1. HSMCs were stimulated with Ang II (1 µM) for 24 h; consequently, DKK1 protein expression was upregulated by 4.26-fold and increased mRNA expression levels of IL-1β, GRP-94 and GRP-78 were also observed, indicating mitochondrial and endoplasmic reticulum stress. DKK1 silencing via small interfering RNA reduced its expression, which was validated by reverse transcription-quantitative PCR. RNA Sequencing was performed in four groups: Negative control (NC), siDKK1, NC-Ang II and siDKK1-Ang II. Differentially expressed genes (DEGs) were identified by DESeq2, and 1,332 co-expressed DEGs were revealed by Venn analysis, enriched in pathways, including 'protein processing in the endoplasmic reticulum'. Robust rank aggregation prioritized key genes, notably single-pass membrane protein with aspartate rich tail 1 (SMDT1), a mitochondrial calcium regulator. The mRNA of SMDT1 was upregulated by Ang II stimulation by 2.78-fold, which was reversed by DKK1 silencing by 0.37-fold. Functional enrichment associated DEGs to viral response, extracellular matrix and cytokine pathways. Protein-protein interaction networks highlighted gene clusters via STRING. In conclusion, the present study investigated the role of DKK1 in Ang II-induced mitochondrial dysfunction in HSMCs. To the best of our knowledge, the present study demonstrated, for the first time, that DKK1/SMDT1 mediated Ang II-induced mitochondrial injury in HSMCs, suggesting this pathway as a potential mechanism. Therefore, the results indicated that DKK1 could serve as a therapeutic target for the prevention of AAA.

DKK1; SMDT1; abdominal aortic aneurysm; angiotensin II; mitochondrial injury.