Activating transcription factor 4 aggravates angiotensin II-induced cell dysfunction in human vascular aortic smooth muscle cells via transcriptionally activating fibroblast growth factor 21

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening disorder worldwide. Fibroblast growth factor 21 (FGF21) was shown to display a high level in the plasma of patients with AAA; however, its detailed functions underlying AAA pathogenesis are unclear. An in vitro AAA model was established in human aortic vascular smooth muscle cells (HASMCs) by angiotensin II (Ang-II) stimulation. Cell counting kit-8, wound healing, and Transwell assays were utilized for measuring cell proliferation and migration. RT-qPCR was used for detecting mRNA expression of FGF21 and activating transcription factor 4 (ATF4). Western blotting was utilized for assessing protein levels of FGF21, ATF4, and markers for the contractile phenotype of HASMCs. ChIP and luciferase reporter assays were implemented for identifying the binding relation between AFT4 and FGF21 promoters. FGF21 and ATF4 were both upregulated in Ang-II-treated HASMCs. Knocking down FGF21 attenuated Ang-II-induced proliferation, migration, and phenotype switch of HASMCs. ATF4 activated FGF21 transcription by binding to its promoter. FGF21 overexpression reversed AFT4 silencing-mediated inhibition of cell proliferation, migration, and phenotype switch. ATF4 transcriptionally upregulates FGF21 to promote the proliferation, migration, and phenotype switch of Ang-II-treated HASMCs.

Fibroblast growth factor 21 in metabolic syndrome

“…showed that the changes in the expression of FGF21 under endoplasmic reticulum (ER) stress are caused by the binding of ATF4 to the FGF21 promoter, thus promoting the transcription of FGF21 ( 40 ). Similar results were also observed in ChIP and luciferase reporter assays, which confirmed that AFT4 can bind to the promoter of FGF21 to promote the expression of FGF21 ( 41 ). Moreover, TRIB3 (Tribbles homolog 3), another cellular stress-inducible gene, could inhibit FGF21 expression by binding to ATF4 at the promoter of FGF21 ( 42 ).…”

Olink Proteomics Platform Reveals Serum Inflammatory Related Protein Biomarkers in Abdominal Aortic Aneurysms

“…[26] In addition, FGF-21 activation exacerbates aortic smooth muscle cell dysfunction, thereby exacerbating AAA. [27] Xie et al found that FGF21 levels were positively correlated with AAA diameter, hypertension rate and hsCRP by measuring FGF-21 expression levels in AAA and normal human serum. [28] Although relevant studies reported that CCL11 and FGF-21 were upregulated in AAA serum, we still wanted to validate them again, so we performed ELISA validation of 5 proteins in control and abdominal aortic aneurysm groups.…”