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Uremic patients are characterized by an increased risk of atherosclerotic cardiovascular diseases. Vascular smooth muscle cell (VSMC) proliferation contributes to neointimal formation, a main pathological feature in atherosclerosis. Activation of CREB/ATF3 signaling is pivotal in VSMC proliferation, yet its role in uremic atherosclerosis is unknown. This study aimed to explore whether CREB/ATF3 signaling is involved in the molecular mechanism underlying neointimal formation in uremia. Treatment of VSMCs with uremic toxin (indoxyl sulfate [IS]) activated cAMP/CREB/ATF3/cyclin D signaling, which was reflected by increased VSMC proliferation. Blocking cAMP/PKA/CREB/ATF3 signaling attenuated the promoting effect of IS on cyclin D1 expression and VSMC proliferation. Loss-of-function and time-dependent experiments showed that ATF3 lies downstream of the CREB signaling. Mutational analysis of cyclin D1 promoter along with chromatin immunoprecipitation assays showed that CREB/ATF3 signaling participated in IS-induced cyclin D transcription. In vivo, phosphorylated CREB (an active form of CREB) and ATF3 were prominently upregulated in the neointima of experimental uremic rats, the atherosclerotic plaques of uremic ApoE-/- mice, and the iliac arteries of uremic patients. Notably, the use of lentivirus to knock down ATF3 in the neointima of balloon-injured arteries could suppress the effect of uremia in vivo, including neointimal formation and cyclin D expression. In this study, we demonstrated that CREB/ATF3-related signaling may be involved in IS-induced VSMC proliferation and the pathogenesis of neointimal formation during uremia. Copyright © 2020 Elsevier B.V. All rights reserved.


Wei-Jan Chen, Ying-Ju Lai, Jia-Lin Lee, Sheng-Tang Wu, Yu-Juei Hsu. CREB/ATF3 signaling mediates indoxyl sulfate-induced vascular smooth muscle cell proliferation and neointimal formation in uremia. Atherosclerosis. 2020 Dec;315:43-54

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PMID: 33227547

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