Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 28;20(6):431-447.
doi: 10.26599/1671-5411.2023.06.002.

Down-regulation of the Smad signaling by circZBTB46 via the Smad2-PDLIM5 axis to inhibit type I collagen expression

Jing Yu  1   2 , Wen-Zhao Yan  3 , Xin-Hua Zhang  1   4 , Bin Zheng  1 , Wen-Sen Pan  2 , Zhan Yang  1   5 , Hong Zhang  5 , Zi-Yuan Nie  6 , Ying Ma  7 , Yang Bai  1 , Long Zhang  1 , Dan-Dan Feng  1 , Jin-Kun Wen  1
Affiliations

Down-regulation of the Smad signaling by circZBTB46 via the Smad2-PDLIM5 axis to inhibit type I collagen expression

Jing Yu et al. J Geriatr Cardiol. .

Abstract

Background: Abnormal type I collagen (COL1) expression is associated with the development of many cardiovascular diseases. The TGF-beta/Smad signaling pathway and circRNAs have been shown to regulate COL1 gene expression, but the underlying molecular mechanisms are still not fully understood.

Methods: Gain- and loss-of-function experiments were prformed to study the effect of circZBTB46 on the expression of alpha 2 chain of type I collagen (COL1A2). Co-immunoprecipitation assay was performed to observe the interaction between two proteins. RNA immunoprecipitation assay and biotin pull-down assay were performed to observe the interaction of circZBTB46 with PDLIM5.

Results: In this study, we investigated the role of circZBTB46 in regulating COL1A2 expression in human vascular smooth muscle cells (VSMCs). We found that circZBTB46 is expressed in VSMCs and that TGF-beta inhibits circZBTB46 formation by downregulating KLF4 expression through activation of the Smad signaling pathway. CircZBTB46 inhibits the expression of COL1A2 induced by TGF-beta. Mechanistically, circZBTB46 mediates the interaction between Smad2 and PDLIM5, resulting in the inhibition of Smad signaling and the subsequent downregulation of COL1A2 expression. Furthermore, we found that the expression of TGF-beta and COL1A2 is decreased, while circZBTB46 expression is increased in human abdominal aortic aneurysm tissues, indicating that circZBTB46-mediated regulation of TGF-beta/Smad signaling and COL1A2 synthesis in VSMCs plays a crucial role in vascular homeostasis and aneurysm development.

Conclusions: CircZBTB46 was identified as a novel inhibitor of COL1 synthesis in VSMCs, highlighting the importance of circZBTB46 and PDLIM5 in regulating TGF-beta/Smad signaling and COL1A2 expression.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Identification of circZBTB46 in human aortic VSMCs.
Figure 2
Figure 2
TGF-beta suppresses the formation of circZBTB46 by downregulating KLF4 expression through Smad signaling.
Figure 3
Figure 3
The involvement of circZBTB46 in regulating the expression of COL1A2 via TGF-beta.
Figure 4
Figure 4
Down-regulation of COL1A2 expression by circZBTB46 through inhibiting the Smad signaling pathway.
Figure 5
Figure 5
The role of circZBTB46 in mediating the interaction between PDLIM5 and Smad2.
Figure 6
Figure 6
PDLIM5 suppresses Smad signaling and COL1A2 expression induced by TGF-beta.
Figure 7
Figure 7
Expression of TGF-beta, circZBTB46, and COL1A2 in human AAA tissues.
See this image and copyright information in PMC

References

    1. Chen Y, Mao C, Gu R, et al Nidogen-2 is a novel endogenous ligand of LGR4 to inhibit vascular calcification. Circ Res. 2022;131:1037–1054. doi: 10.1161/CIRCRESAHA.122.321614. - DOI - PubMed
    1. Mao C, Ma Z, Jia Y, et al Nidogen-2 maintains the contractile phenotype of vascular smooth muscle cells and prevents neointima formation via bridging Jagged1-Notch3 signaling. Circulation. 2021;144:1244–1261. doi: 10.1161/CIRCULATIONAHA.120.053361. - DOI - PubMed
    1. Koga Y, Pelizzola M, Cheng E, et al Genome-wide screen of promoter methylation identifies novel markers in melanoma. Genome Res. 2009;19:1462–1470. doi: 10.1101/gr.091447.109. - DOI - PMC - PubMed
    1. Mori K, Enokida H, Kagara I, et al CpG hypermethylation of collagen type I alpha 2 contributes to proliferation and migration activity of human bladder cancer. Int J Oncol. 2009;34:1593–1602. doi: 10.3892/ijo_00000289. - DOI - PubMed
    1. Andreassi MG, Della Corte A Genetics of bicuspid aortic valve aortopathy. Curr Opin Cardiol. 2016;31:585–592. doi: 10.1097/HCO.0000000000000328. - DOI - PubMed

LinkOut - more resources