Activating transcription factor 3 inhibits angiotensin II‑induced cardiomyocyte viability and fibrosis by activating the transcription of cysteine‑rich angiogenic protein 61

Zhang,Yu; Wu,Heming; Luo,Honghui; Luo,Yiqun; Huang,Cong

doi:10.3892/mmr.2022.12852

Activating transcription factor 3 inhibits angiotensin II‑induced cardiomyocyte viability and fibrosis by activating the transcription of cysteine‑rich angiogenic protein 61

Authors:
- Yu Zhang
- Heming Wu
- Honghui Luo
- Yiqun Luo
- Cong Huang
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Affiliations: Department of General Practice, Meizhou People's Hospital, Meizhou, Guangdong 514031, P.R. China, Central Laboratory, Meizhou People's Hospital, Meizhou, Guangdong 514031, P.R. China
Published online on: September 12, 2022 https://doi.org/10.3892/mmr.2022.12852
Article Number: 336
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Depletion of activating transcription factor 3 (ATF3) expression has previously been reported to promote hypertrophy, dysfunction and fibrosis in stress overload‑induced hearts; however, the mechanism involved remains poorly understood. In the present study, the mechanism underlying the activation of cysteine‑rich angiogenic protein 61 (Cyr61) by ATF3 in hyperproliferative and fibrotic human cardiac fibroblasts (HCFs), induced by angiotensin II (Ang II), was evaluated. The mRNA and protein expression levels of ATF3 and Cyr61 were assessed using reverse transcription‑quantitative PCR and western blotting, respectively. The Cell Counting Kit‑8 assay was used to assess cell viability. Cell migration was assessed using the wound healing assay and western blotting, whereas the extent of cell fibrosis was evaluated using immunofluorescence staining and western blotting. The binding site of ATF3 to the Cyr61 promoter was predicted using the JASPAR database, and verified using luciferase reporter and chromatin immunoprecipitation assays. The results demonstrated that the mRNA and protein expression levels of ATF3 were significantly upregulated in Ang II‑induced HCFs. Overexpression of ATF3 significantly inhibited the Ang II‑induced viability, migration and fibrosis of HCFs, whereas ATF3 knockdown mediated significant opposing effects. Mechanistically, ATF3 was demonstrated to transcriptionally activate Cyr61. Cyr61 silencing was subsequently revealed to reverse the effects of ATF3 overexpression on HCFs potentially via regulation of the TGF‑β/Smad signaling pathway. The results of the present study suggested that ATF3 could suppress HCF viability and fibrosis via the TGF‑β/Smad signaling pathway by activating the transcription of Cyr61.

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