Novel Zinc Finger Transcription Factor ZFP580 Facilitates All-Trans Retinoic Acid -Induced Vascular Smooth Muscle Cells Differentiation by Rarα-Mediated PI3K/Akt and ERK Signaling

Abstract

Background/Aims: Phenotypic switching of vascular smooth muscle cells (VSMC) plays a vital role in the development of vascular diseases. All-trans retinoic acid (ATRA) is known to regulate VSMC phenotypes. However, the underlying mechanisms remain completely unknown. Here, we have investigated the probable roles and underlying mechanisms of the novel C2H2 zinc finger transcription factor ZFP580 on ATRA-induced VSMC differentiation. Methods: VSMCs were isolated, cultured, and identified. VSMCs were infected with an adenovirus encoding ZFP580 or Ad-siRNA to silence ZFP580. The expression levels of ZFP580, SMα-actin, SM22α, SMemb, RARα, RARβ, and RARγ were assayed by Q-PCR and western blot. A rat carotid artery injury model and morphometric analysis of intimal thickening were also used in this study. Results: ATRA caused a significant reduction of VSMC proliferation and migration in a doseand time-dependent manner. Moreover, it promoted VSMC differentiation by enhancing expression of differentiation markers and reducing expression of dedifferentiation markers. This ATRA activity was accompanied by up-regulation of ZFP580, with concomitant increases in RARα expression. In contrast, silencing of the RARα gene or inhibiting RARα with its antagonist Ro41-5253 abrogated the ATRA-induced ZFP580 expression. Furthermore, ATRA binding to RARα induced ZFP580 expression via the PI3K/Akt and ERK pathways. Adenovirusmediated overexpression of ZFP580 promoted VSMC differentiation by enhancing expression of SM22α and SMα-actin and reducing expression of SMemb. In contrast, silencing ZFP580 dramatically reduced the expression of differentiation markers and increased expression of dedifferentiation markers. The classic rat carotid artery balloon injury model demonstrated that ZFP580 inhibited proliferation and intimal hyperplasia in vivo. Conclusion: The novel zinc finger transcription factor ZFP580 facilitates ATRA-induced VSMC differentiation by the RARα-mediated PI3K/Akt and ERK signaling pathways. This might represent a novel mechanism of regulation of ZFP580 by ATRA and RARα, which is critical for understanding the biological functions of retinoids during VSMC phenotypic modulation.

Phytoestrogenic Effects of Blackcurrant Anthocyanins Increased Endothelial Nitric Oxide Synthase (eNOS) Expression in Human Endothelial Cells and Ovariectomized Rats

“…Retinoids such as tretinoin are important regulators of cell division and proliferation. Its cosmetic effects on the skin are well known, and several studies have demonstrated the effects of tretinoin on blood vessels [43,44,45]. The current results suggest that BCE may exert an effect similar to that of tretinoin on HUVECs.…”

Mecp2 promotes the anti‐inflammatory effect of alpinetin via epigenetic modification crosstalk

“…Alpinetin is a traditional Chinese drug isolated from the plant Alpinia katsumadai Hayata , which has anti‐bacterial, anti‐oxidant, and anti‐inflammatory effects 10,11 . In a previous study, we assessed the anti‐inflammatory effect of alpinetin and confirmed that this drug could inhibit the expression of NF‐κB and extracellular signal‐regulated kinase family members through the peroxisome proliferator‐activated receptors (PPAR), affecting the expression of IL‐6 and TNF‐α 12,13 . Moreover, we found that PPAR activation induced by alpinetin can further promote the synthesis and modification activity of DNA methyltransferase DNMT3A in the nucleus of RAW 246.7 (the macrophage cell line), thus promoting the methylated modification of the IL‐6 promoter and blocked the binding of transcription factors.…”

“…10,11 In a previous study, we assessed the anti-inflammatory effect of alpinetin and confirmed that this drug could inhibit the expression of NF-κB and extracellular signal-regulated kinase family members through the peroxisome proliferator-activated receptors (PPAR), affecting the expression of IL-6 and TNFα. 12,13 Moreover, we found that PPAR activation induced by alpinetin can further promote the synthesis and modification activity of DNA methyltransferase DNMT3A in the nucleus of RAW 246.7 (the macrophage cell line), thus promoting the methylated modification of the IL-6 promoter and blocked the binding of transcription factors. Therefore, the PPAR/DNMT3A pathway is considered the main molecular mechanism involved in reversing inflammatory organ damage by alpinetin.…”

miR-18a-5p Promotes Proliferation and Migration of Vascular Smooth Muscle Cells by Activating the AKT/Extracellular Regulated Protein Kinases (ERK) Signaling Pathway

“…Humphreys et al reported that miR-18a-5p regulates tumor cell cycle progression by targeting CDC42 , but whether CDC42 is involved in the VSMCs cycle control is unclear [ 31 ]. Further research is needed to determine the role of upstream regulatory proteins of the AKT/ERK signaling pathway, including phosphatidylinositol-3-hydroxykinase [ 32 ], platelet-derived growth factor B [ 33 ], and mitogen-activated protein kinase [ 34 ] in mediating the impact of miR-18a-5p on the abnormal VSMCs biological functions.…”