Regulatory crosstalk between KLF5, miR-29a and Fbw7/CDC4 cooperatively promotes atherosclerotic development

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2018-02, Vol.1864 (2), p.374-386
• Main Authors: Zheng, Bin, Zheng, Cui-ying, Zhang, Yu, Yin, Wei-na, Li, Yong-hui, Liu, Chao, Zhang, Xin-hua, Nie, Chan-juan, Zhang, Hong, Jiang, Wen, Liu, Shu-feng, Wen, Jin-kun
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Animals; Aorta - cytology; Atherosclerosis; Atherosclerosis - metabolism; Biomarkers - metabolism; Cell Differentiation; Cell Proliferation; Cells, Cultured; F-Box-WD Repeat-Containing Protein 7 - genetics; F-Box-WD Repeat-Containing Protein 7 - metabolism; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Lipoproteins, LDL - metabolism; Macrophages - metabolism; Mice; Mice, Knockout, ApoE; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; NIH 3T3 Cells; Smooth, muscle; Ubiquitination
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.10.021

Atherogenesis is a chronic inflammatory process that involves complex interactions between endothelial dysfunction, lipid deposition and vascular smooth-muscle cell (VSMC) proliferation. However, the molecular mechanism is still unclear. We found that a pro-atherosclerotic factor (oxLDL) induced the expression of Krüppel-like factor 5 (KLF5), which in turn increased miR-29a expression levels. The increased miR-29a was retained within HASMCs and down-regulated Fbw7/CDC4 expression by targeting the 3´UTR of Fbw7/CDC4, subsequently increasing KLF5 stability by reducing the Fbw7/CDC4-dependent ubiquitination of KLF5, forming a positive feedback loop to enhance VSMC proliferation and promote atherogenesis. These results indicate a potentially important role for the oxLDL-activated feedback mechanism in VSMC proliferation and atherogenesis. Suppression of miR-29a may be an effective way to attenuate atherosclerosis. In conclusion, our data are the first to reveal that the regulatory crosstalk between KLF5, miR-29a, and Fbw7/CDC4 cooperatively promotes atherosclerotic development. •miR-29a might contribute to atherosclerosis development at least partially through increasing VSMC proliferation.•KLF5 is an important factor that mediates atherosclerosis promoted by miR-29a.•miR-29a increases KLF5 stability by directly targeting Fbw7/CDC4.•miR-29a is most likely a biomarker for CAD.