P21‑activated kinase 1 mediates angiotensin II‑induced differentiation of human atrial fibroblasts via the JNK/c‑Jun pathway.

Yafei Zhou, Ying Xie, Tao Li, Peng Zhang, Tangting Chen, Zhongcai Fan, Xiaoqiu Tan

Molecular medicine reports 2021 Mar

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Cardiac fibrosis is a common pathophysiological condition involved in numerous types of cardiovascular disease. The renin‑angiotensin system, particularly angiotensin II (AngII), serves an important role in cardiac fibrosis and remodeling. Furthermore, p21‑activated kinase 1 (PAK1) is a highly conserved serine/threonine protein kinase, which is abundantly expressed in all regions of the heart. However, the role of PAK1 in AngII‑mediated activation of cardiac fibroblasts remains unknown. Therefore, the present study aimed to investigate the role of PAK1 in cardiac fibroblasts and its underlying mechanisms. Human cardiac fibroblasts (HCFs) were cultured and treated with PAK1 inhibitor IPA‑3 or transduced with PAK1 short hairpin (sh)RNA by lentiviral particles to silence PAK1 expression levels. Subsequently, the cell proliferation and migration abilities of the HCFs were determined. Western blot analysis was used to detect the phosphorylation status of Janus kinase (JNK) and c‑Jun. A Cell Counting Kit‑8 assay showed that PAK1 inhibition following treatment of HCFs with 5 µM IPA‑3 or PAK1‑shRNA, significantly attenuated AngII‑induced proliferation of fibroblasts. In addition, wound healing and Transwell migration assays demonstrated that inhibition of PAK1 significantly inhibited AngII‑induced cell migration. Finally, decreased PAK1 expression levels downregulated AngII‑mediated upregulation of α‑smooth muscle actin (α‑SMA), collagen I, phosphorylated (p)‑JNK and p‑c‑Jun, a downstream molecule of JNK signaling. These findings indicate that PAK1 contributes to AngII‑induced proliferation, migration and transdifferentiation of HCFs via the JNK/c‑Jun pathway.

Citation

Yafei Zhou, Ying Xie, Tao Li, Peng Zhang, Tangting Chen, Zhongcai Fan, Xiaoqiu Tan. P21‑activated kinase 1 mediates angiotensin II‑induced differentiation of human atrial fibroblasts via the JNK/c‑Jun pathway. Molecular medicine reports. 2021 Mar;23(3)