The SNP rs4591246 in pri-miR-1-3p is associated with abdominal aortic aneurysm risk by regulating cell phenotypic transformation via the miR-1-3p/TLR4 axis

• Published in: International immunopharmacology Vol. 118; p. 110016
• Main Authors: Li, Tan, Jing, Jingjing, Sun, Liping, Gong, Yuehua, Yang, Jun, Ma, Chunyan, Yuan, Yuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2023
• Subjects: Abdominal aortic aneurysm; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - metabolism; Biomarker; Genotype; Humans; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Polymorphism, Single Nucleotide; Single nucleotide polymorphism; Toll-Like Receptor 4 - genetics; Vascular smooth muscle cell; Vascular smooth muscle cell; Biomarker; MicroRNA; Single nucleotide polymorphism; Abdominal aortic aneurysm
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2023.110016

•The rs4591246 variant genotype and reduced expression of tissue miR-1-3p are associated with increased AAA risk.•The rs4591246 polymorphism can affect mature miR-1-3p expression and TLR4 is identified as a crucial target of miR-1-3p.•In Ang II-induced HASMCs, rs4591246 variant genotype augments cell phenotypic transformation through the miR-1-3p/TLR4 axis. Emerging evidence reveals that single nucleotide polymorphism (SNP) within miRNAs can affect the risk of cardiovascular diseases. However, the role of miRNA SNPs in abdominal aortic aneurysm (AAA) is unclear. This study aimed to determine the association between SNPs in pri-miR-1-3p and AAA risk, as well as its underlying molecular mechanism. SNP genotyping was performed in 335 AAA patients and 335 controls using the KASP method and tissue miR-1-3p expression was measured by qRT-PCR. The biological effects of significant SNP were validated using in vitro studies. We found that the rs4591246 variant genotype was correlated with increased AAA risk and tissue miR-1-3p expression was reduced in AAA patients as compared with control subjects. An in silico approach predicted that the rs4591246 polymorphism altered the secondary structure and stability of pri-miR-1-3p, and in vitro evidence suggested that the rs4591246 polymorphism affected mature miR-1-3p expression. And luciferase assays verified TLR4 as a direct target gene of miR-1-3p. Further functional experiments demonstrated that the rs4591246 variant genotype could promote Ang II-induced cell phenotypic switching by suppressing mature miR-1-3p expression and in turn upregulating TLR4 expression, but this effect was rescued in the presence of TLR4 siRNA. In conclusion, as a promising genetic biomarker for AAA susceptibility, the SNP rs4591246 may exert its effects on AAA risk by regulating cell phenotypic transformation via the miR-1-3p/TLR4 axis.