Regulatory crosstalk between KLF5, miR-29a and Fbw7/CDC4 cooperatively promotes atherosclerotic development |
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Authors: | Bin Zheng Cui-ying Zheng Yu Zhang Wei-na Yin Yong-hui Li Chao Liu Xin-hua Zhang Chan-juan Nie Hong Zhang Wen Jiang Shu-feng Liu Jin-kun Wen |
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Affiliation: | 1. Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017,China;2. The Laboratory of the Animal Center of Hebei Medical University, Shijiazhuang 050017, China;3. Paediatric Department, Handan first hospital, Handan 056000, China;4. Hebei Center for Disease Control and Prevention, Shijiazhuang, 050000, China |
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Abstract: | 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. |
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Keywords: | Fbw7/CDC4 F-box and WD40 repeat domain-containing 7 HASMC Human aortic smooth muscle cells CAD Coronary artery disease KLF Krüppel-like factor CBP CREB-binding protein miR microRNA oxLDL Oxidized low-density lipoprotein qRT-PCR Quantitative real-time polymerase chain reaction UTR Untranslated regions VSMCs Vascular smooth muscle cells Atherosclerosis Smooth, muscle Ubiquitination Cell proliferation microRNA |
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