Dec1 Deficiency Suppresses Cardiac Perivascular Fibrosis Induced by Transverse Aortic Constriction

Le, Hue Thi; Sato, Fuyuki; Kohsaka, Akira; Bhawal, Ujjal K.; Nakao, Tomomi; Muragaki, Yasuteru; Nakata, Masao

doi:10.3390/ijms20194967

Cited by 13 publications

(17 citation statements)

References 36 publications

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“…Although Dec1 is well known as an oncogene in tumors ( Nakamura et al, 2008 ; Feige et al, 2011 ; Sato et al, 2016 ; Jia et al, 2018 ), the present study also adds to a growing body of molecular evidence linking Dec1 to hypoxia-associated diseases ( Nishiyama et al, 2012 ; Wu et al, 2017 ; Huang et al, 2018 ; Nakashima et al, 2018 ; Le et al, 2019 ). For example, Hue et al previously reported that Dec1 expression was significantly upregulated in human cardiac hypertrophy and myocardial infarction, while Dec1 deficiency suppressed cardiac perivascular fibrosis and attenuated expressions of p21, TGF-β1, pSmad3, and TNF-α in transverse aortic constriction treated mouse models ( Le et al, 2019 ). Although the potential mechanism remained to be specified, this study provided key findings regarding Dec1 in transverse aortic constriction induced by hypoxia, inflammation, and fibrosis in cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 80%

“…Differentiated embryo-chondrocyte expressed gene 1 is dysregulated by hypoxia-driven responses and plays important roles in cell death and survival ( Park and Park, 2012 ; Sato et al, 2016 ; Jia et al, 2018 ; Nakashima et al, 2018 ; Le et al, 2019 ). Therefore, the hnPAECs were treated with hypoxia.…”

Section: Resultsmentioning

confidence: 99%

“…Differentiated embryo-chondrocyte expressed gene 1 plays an important role in cell proliferation and apoptosis under various oxidative stress and inflammatory stimuli ( Seino et al, 2015 ; Jia et al, 2018 ; Ming et al, 2018 ; Le et al, 2019 ). Therefore, the effects of Dec1 on proliferation and apoptosis of PAECs under hypoxia were examined.…”

Section: Resultsmentioning

confidence: 99%

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Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Liu

et al. 2021

Front. Cell Dev. Biol.

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Background: The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying this hypoxic disease has not been fully elucidated.Methods: Bioinformatics was adopted to screen out the key hypoxia-related genes in PAH. Gain- and loss-function assays were then performed to test the identified hypoxic pathways in vitro. Human PAECs were cultured under hypoxic (3% O2) or normoxic (21% O2) conditions. Hypoxia-induced changes in apoptosis and proliferation were determined by flow cytometry and Ki-67 immunofluorescence staining, respectively. Survival of the hypoxic cells was estimated by cell counting kit-8 assay. Expression alterations of the target hypoxia-related genes, cell cycle regulators, and apoptosis factors were investigated by Western blot.Results: According to the Gene Expression Omnibus dataset (GSE84538), differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ (Dec1-PPARγ) axis was defined as a key hypoxia-related signaling in PAH. A negative correlation was observed between Dec1 and PPARγ expression in patients with hypoxic PAH. In vitro observations revealed an increased proliferation and a decreased apoptosis in PAECs under hypoxia. Furthermore, hypoxic PAECs exhibited remarkable upregulation of Dec1 and downregulation of PPARγ. Dec1 was confirmed to be crucial for the imbalance of proliferation and apoptosis in hypoxic PAECs. Furthermore, the pro-surviving effect of hypoxic Dec1 was mediated through PPARγ inhibition.Conclusion: For the first time, Dec1-PPARγ axis was identified as a key determinant hypoxia-modifying signaling that is necessary for the imbalance between proliferation and apoptosis of PAECs. These novel endothelial signal transduction events may offer new diagnostic and therapeutic options for patients with hypoxic PAH.

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…Inflammation has been known to precede cardiac fibrosis in TAC mice 36 ; therefore, we investigated the accumulation of T cells and macrophages in the heart after TAC. In the immunohistochemical analysis of CD3 and CD68 in heart sections, the infiltration of T cells and macrophages occurred in TAC mice, and they were both observed in the cardiac tissues after TAC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

Methatham

Tomida

Kimura

et al. 2021

Sci Rep

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In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

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“…Human differentiated embryonic chondrocyte expressed gene 1 (DEC1), also known as BHLHE40/Stra13/Sharp2, belongs to a structurally distinct class of basic helix- loop-helix (bHLH) proteins ( Sato et al, 2016 ). It has been considered as a signaling mediator of diverse physiological processes including circadian rhythmicity, immunity, proliferation, apoptosis, senescence, tumorigenesis, and fibrosis ( Honma et al, 2002 ; Qian et al, 2008 ; Gallo et al, 2018 ; Jia et al, 2018 ; Jarjour et al, 2019 ; Le et al, 2019 ; Li et al, 2019 ). A previous study has reported that Dec1 deficiency suppressed cardiac perivascular fibrosis in hypertrophic hearts induced by transverse aortic constriction (TAC), resulting in preserved cardiac function ( Le et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

Zou

et al. 2022

Front. Pharmacol.

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Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1−/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1−/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.

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Dec1 Deficiency Suppresses Cardiac Perivascular Fibrosis Induced by Transverse Aortic Constriction

Cited by 13 publications

References 36 publications

Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

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