Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Zhejiang, Ningbo, China.
J Vasc Res. 2021;58(2):108-120. doi: 10.1159/000512595. Epub 2021 Jan 25.
Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and specific anti-TRPM7 small interfering RNA (si-RNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.
动脉重构是高血压的病理学基础之一。我们之前的研究表明，瞬时受体电位 melastatin 7（TRPM7）可加重主动脉缩窄（TAC）模型中压力超负荷引起的血管外膜重构。在这项研究中，我们试图探索机械拉伸应激（MSS）刺激下血管外膜成纤维细胞（AFs）中 TRPM7 的功能表达及其下游信号。在 20% MSS 刺激的 AFs 中，TRPM7 的表达上调，同时伴有向细胞质易位。同时，α-平滑肌肌动蛋白（α-SMA）的表达也增加，α-SMA 是 AF 向肌成纤维细胞（MFs）转化的标志物。此外，MSS 处理后的 AF 条件培养基可引起巨噬细胞的显著迁移，并且含有高水平的单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α）。使用 TRPM7 抑制剂 2-氨基乙氧基二苯硼酸盐（2-APB）和特异性抗 TRPM7 小干扰 RNA（si-RNA-TRPM7）的药理学和 RNA 干扰方法可显著阻断这些变化。进一步的探索揭示，抑制 TRPM7 可降低 MSS 刺激的 AFs 中 p38MAPK（p38MAPK）和 c-Jun N-末端激酶（JNK）的磷酸化。此外，抑制 p38MAPK 或 JNK 的磷酸化也可减轻 MSS 诱导的α-SMA 表达和炎症因子的分泌。这些观察结果表明，激活的 TRPM7 通过 p38MAPK/JNK 通路参与 MSS 刺激下 AFs 的表型转化和炎症作用，并提示 TRPM7 可能是高血压血流动力学变化引起的血管重构的潜在治疗靶点。
