All-Trans Retinoic Acid Attenuates Hypoxia-Induced Injury in NRK52E Cells via Inhibiting NF-κB/VEGF and TGF-β2/VEGF Pathway

Xu, Yong; Gao, Ai-Mei; Ji, Lijuan; Li, Xing; Zhong, Lili; Li, Hailun; Zheng, Donghui

doi:10.1159/000438624

Cited by 8 publications

(9 citation statements)

References 19 publications

(23 reference statements)

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“…Retinoids are natural and synthetic derivatives of vitamin A (retinol) [9]. The discovery of all-trans retinoic acid (ATRA) as the carboxylic acid form of vitamin A led to studies that ascribed virtually all of the biological effects of vitamin A to this natural retinoid [12]. Thus, ATRA plays a vital role in normal embryogenesis and in such postnatal processes as skin and epithelial homeostasis, hematopoiesis, and spermatogenesis [34].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it was found that retinoids could inhibit inflammation, thrombosis, platelet adhesion and aggregation, and stimulate fibrinolysis [11]. Predominantly, all-trans retinoic acid (ATRA) and its stereoisomer 9-cis retinoic acid (9cRA) were found to be very potent metabolites of retinol, exerting pleiotropic effects on many different biological processes [12]. These effects are mediated by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are ligand-dependent transcription factors that belong to the nuclear receptor superfamily [13].…”

Section: Introductionmentioning

confidence: 99%

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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

Wei

Zhang

Han

et al. 2018

Cell Physiol Biochem

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wei

Zhang

Han

et al. 2018

Cell Physiol Biochem

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“…On the basis of the known role of ATRA in attenuating hypoxia-induced injury in non-trasformed cells [ 28 ], its possible role in counteracting the effect of low oxygen availability in non-invasive breast cancer cells was investigated. MCF10DCIS cells were then cultured under moderate hypoxia for 96 h in the presence of 1 μM ATRA, revealing an agonist induced decrease of cell growth similar to that observed under normoxia (Fig.…”

Section: Resultsmentioning

confidence: 99%

Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non-invasive breast tumor derived cells

et al. 2018

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BackgroundThe presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women.MethodsBy using a DCIS-derived cell line, we evaluated the effects of low oxygen availability on malignant features of non-invasive breast tumor cells and the possible role of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug, in counteracting the effects of hypoxia. The involvement of the β2 isoform of PI-PLC (PLC-β2), an ATRA target in myeloid leukemia cells, was also investigated by specific modulation of the protein expression.ResultsWe demonstrated that moderate hypoxia is sufficient to induce, in DCIS-derived cells, motility, epithelial-to-mesenchymal transition (EMT) and expression of the stem cell marker CD133, indicative of their increased malignant potential.Administration of ATRA supports the epithelial-like phenotype of DCIS-derived cells cultured under hypoxia and keeps down the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. We also found that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia is in part mediated by PLC-β2, responsible to counteract the effects of low oxygen availability on CD133 levels.ConclusionsOverall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and we identified in ATRA, currently used in treatment of acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions showing hypoxic areas.

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“…Ang and VEGF are two major proangiogenic factors that synergistically promote angiogenesis [27]. The expression level of VEGF is significantly increased in pathological conditions such as hypoxia and injury [28,29]. Studies have Fig.…”

Section: Discussionmentioning

confidence: 99%

DHA Attenuates Hypoxia/Reoxygenation Injury by Activating SSeCKS in Human Cerebrovascular Pericytes

Fang

Qiu

et al. 2019

Neurochem Res

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Docosahexaenoic acid (DHA) can alleviate cerebral ischemia/reperfusion injury by reducing blood-brain barrier permeability and maintaining its integrity, accompanied by an increased Ang-1/Ang-2 ratio; however, the underlying mechanisms of these effects remain unclear. Src-suppressed C kinase substrates (SSeCKS), a substrate of protein kinase C, plays an important role in maintaining cell junctions and cell morphology and regulating cell permeability. However, whether DHA can increase SSeCKS expression and then mediate the Ang-1/Ang-2 ratio still needs to be studied. Human cerebrovascular pericytes (HBVPs) cultured in vitro were divided into groups, treated with or without DHA along with SSeCKS siRNA to knockdown SSeCKS expression, and then subjected to 24 h of hypoxia followed by 6 h of reoxygenation. Cell viability; lactate dehydrogenase (LDH) release; and Ang-1, Ang-2 and VEGF activity were detected by using ELISA kits. The apoptosis rate was assessed by TUNEL flow cytometry. Expression of the SSeCKS, Ang-1, Ang-2 and VEGF proteins was evaluated by western blotting. Pretreatment with 10 μM or 40 μM DHA efficiently attenuated hypoxia/reoxygenation (H/R) injury by activating SSeCKS to increase the Ang-1/Ang-2 ratio and downregulate VEGF expression in HBVPs, as evidenced by decreased LDH release and apoptotic rates and increased HBVPs viability. Meanwhile, after we used SSeCKS siRNA to knock down SSeCKS protein expression, the protective effect of DHA on HBVPs following H/R injury was reversed. In conclusion, DHA can activate SSeCKS to increase the Ang-1/Ang-2 ratio and downregulate VEGF expression in HBVPs, thus reducing H/R injury.

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All-Trans Retinoic Acid Attenuates Hypoxia-Induced Injury in NRK52E Cells via Inhibiting NF-κB/VEGF and TGF-β2/VEGF Pathway

Cited by 8 publications

References 19 publications

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

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

Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non-invasive breast tumor derived cells

DHA Attenuates Hypoxia/Reoxygenation Injury by Activating SSeCKS in Human Cerebrovascular Pericytes

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