Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang 110001, China; Clinical Medical Research Center of Imaging in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, China.
Int Immunopharmacol. 2023 May;118:110016. doi: 10.1016/j.intimp.2023.110016. Epub 2023 Mar 15.
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.
新兴证据表明，miRNA 中的单核苷酸多态性 (SNP) 可影响心血管疾病的风险。然而，miRNA SNPs 在腹主动脉瘤 (AAA) 中的作用尚不清楚。本研究旨在确定 pri-miR-1-3p 中的 SNP 与 AAA 风险之间的关联及其潜在的分子机制。采用 KASP 方法对 335 例 AAA 患者和 335 例对照进行 SNP 基因分型，并通过 qRT-PCR 测定组织 miR-1-3p 表达。使用体外研究验证显著 SNP 的生物学效应。我们发现，与对照组相比，rs4591246 变异基因型与 AAA 风险增加相关，并且 AAA 患者的组织 miR-1-3p 表达降低。计算机预测发现 rs4591246 多态性改变了 pri-miR-1-3p 的二级结构和稳定性，体外证据表明 rs4591246 多态性影响成熟 miR-1-3p 的表达。荧光素酶测定验证了 TLR4 是 miR-1-3p 的直接靶基因。进一步的功能实验表明，rs4591246 变异基因型可通过抑制成熟 miR-1-3p 表达，从而上调 TLR4 表达，促进 Ang II 诱导的细胞表型转换，但在 TLR4 siRNA 存在的情况下，这种作用得到挽救。总之，作为 AAA 易感性的有前途的遗传生物标志物，SNP rs4591246 可能通过 miR-1-3p/TLR4 轴调节细胞表型转化来发挥其对 AAA 风险的影响。
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