Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China.
Int J Biol Sci. 2024 Jan 1;20(1):29-46. doi: 10.7150/ijbs.83091. eCollection 2024.
Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to β-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.
胸主动脉夹层 (TAD) 是一种发病率和死亡率都很高的心血管疾病。血管平滑肌细胞 (VSMCs) 在 TAD 的形成中起着至关重要的作用。最近的研究表明，细胞外 S100A4 可能参与 VSMCs 的调节。然而，其潜在的机制仍不清楚。因此，本研究探讨了 S100A4 在 VSMCs 调节和 TAD 形成中的作用。
基于 Gene Expression Synthesis 数据库中主动脉夹层的转录组数据，筛选出枢纽基因。通过饮用 β-氨基丙腈单富马酸盐，将三周龄的 S100A4 过表达 (AAV9- S100A4 OE) 和 S100A4 敲低 (AAV9- S100A4 KD) 小鼠暴露于水中 28 天，建立小鼠 TAD 模型。结果显示，S100A4 是主动脉夹层的枢纽基因。此外，S100A4 的过表达加剧，而 S100A4 的抑制显著改善了 TAD 的进展。在 TAD 模型中，S100A4 加剧了 VSMCs 的表型转化。此外，赖氨酰氧化酶 (LOX) 是 S100A4 在 TAD 中的一个重要靶标。S100A4 与 VSMCs 中的 LOX 相互作用，降低成熟 LOX (m-LOX) 的水平，减少弹性纤维的沉积，从而破坏细胞外基质的动态平衡，促进 TAD 的发展。人主动脉组织中的弹性纤维沉积与 S100A4 的表达呈负相关，而 S100A4 与 LOX 呈负相关。
我们的数据表明，S100A4 调节 TAD 的进展，通过与 LOX 相互作用诱导 m-LOX 的溶酶体降解，并减少弹性纤维的沉积，从而导致 TAD 细胞外基质动态平衡的破坏。这些发现表明，S100A4 可能是预防和治疗 TAD 的新靶点。
