Transcription factors: key regulatory targets of vascular smooth muscle cell in atherosclerosis

Abstract

Atherosclerosis (AS), leading to gradual occlusion of the arterial lumen, refers to the accumulation of lipids and inflammatory debris in the arterial wall. Despite therapeutic advances over past decades including intervention or surgery, atherosclerosis is still the most common cause of cardiovascular diseases and the main mechanism of death and disability worldwide. Vascular smooth muscle cells (VSMCs) play an imperative role in the occurrence of atherosclerosis and throughout the whole stages. In the past, there was a lack of comprehensive understanding of VSMCs, but the development of identification technology, including in vivo single-cell sequencing technology and lineage tracing with the CreERT2-loxP system, suggests that VSMCs have remarkable plasticity and reevaluates well-established concepts about the contribution of VSMCs. Transcription factors, a kind of protein molecule that specifically recognizes and binds DNA upstream promoter regions or distal enhancer DNA elements, play a key role in the transcription initiation of the coding genes and are necessary for RNA polymerase to bind gene promoters. In this review, we highlight that, except for environmental factors, VSMC genes are transcriptionally regulated through complex interactions of multiple conserved cis-regulatory elements and transcription factors. In addition, through a series of transcription-related regulatory processes, VSMCs could undergo phenotypic transformation, proliferation, migration, calcification and apoptosis. Finally, enhancing or inhibiting transcription factors can regulate the development of atherosclerotic lesions, and the downstream molecular mechanism of transcriptional regulation has also been widely studied.

Participation of Krüppel-like Factors in Atherogenesis

“…In endothelial cells, KLF5 has been shown to play a pathogenic role in the development of atherosclerosis [ 50 , 51 ]. KLF5 plays an important role in the proliferation of vascular smooth muscle cells (VSMCs) and is induced in response to vascular injury.…”

“…Activation of the PI3K/Akt and MAPK pathways leads to increased KLF5 gene expression in VSMCs. KLF5 mRNA levels increase rapidly in neointimal VSMCs after vascular injury [ 50 , 68 , 69 ].…”

Editorial: Transcription factors and arrhythmogenesis

“…The present Research Topic, entitled "Transcription Factors and Arrhythmogenesis" aims at highlighting the functional role of gene regulatory networks of cardiac enriched transcription factors and their target genes in the pathophysiology of cardiac arrhythmias. Generally speaking, transcription factors bind to the promoter regions of target genes and regulate their expression (Ciccarelli et al, 2011;Larsen et al, 2020;Henley and Koehler, 2021;Tang et al, 2021;de Mattos et al, 2022;Xiao et al, 2022;Jiang and Qian, 2023;Yu et al, 2023;Zhao et al, 2023). Transcription factors can regulate arrhythmogenesis by modulating the expression of genes involved in the cardiac conduction system and/or myocardial structures, as well as through indirect effects on ionic currents, calcium homeostasis, inflammation, oxidative stress, and cardiac remodeling (Liang et al, 2015;Lu et al, 2015;Crespo-Garcia et al, 2022).…”

Hydrogen Sulfide and Oxygen Homeostasis in Atherosclerosis: A Systematic Review from Molecular Biology to Therapeutic Perspectives

“…Additionally, H 2 S has been shown to inhibit VSMC calcification by suppressing the Wnt/beta-catenin pathway [95]. Studies have demonstrated that H 2 S can regulate cell proliferation in VSMCs by inhibiting cell cycle progression and inducing cell cycle arrest by downregulating the expression of cyclin D1 and CDK4, critical regulators of the G1 phase [96]. Additionally, H 2 S has been shown to induce apoptosis in VSMCs by activating the caspase-dependent apoptotic pathway [97].…”