Dipeptidyl peptidase-4 inhibition prevents vascular aging in mice under chronic stress: Modulation of oxidative stress and inflammation

Xin, Minglong; Jin, Xin; Cui, Xiang-Dan; Jin, Chunzi; Piao, Limei; Wan, Ying; Xu, Shengnan; Zhang, Shengming; Yue, Xueling; Wang, Hailong; Nan, Yongshan; Cheng, Xianwu

doi:10.1016/j.cbi.2019.108842

Cited by 35 publications

(41 citation statements)

References 46 publications

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“…cathepsins (cat) are matrix degradation proteases that are considered to modulate vascular aging and remodeling. For example, Xin et al (45) revealed that matrix metalloproteinase (MMP)-2, MMP-9, cat S and cat K were upregulated in response to chronic stress-induced aortic senescence, accompanied by oxidative and inflammatory responses in human umbilical vein endothelial cells. The peroxisome proliferator-activated receptor-γ is upstream of cat S signaling in pulmonary vascular remodeling (46).…”

Section: Discussionmentioning

confidence: 99%

lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195

et al. 2020

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FGd5 antisense rna 1 (FGd5-aS1) is a long non-coding rna in acute myocardial infarction (aMi), which is primarily caused by myocardial ischemia-hypoxia. retinoid acid receptor-related orphan receptor α (rora) is a key protector in maintaining heart function. However, the roles of FGd5-aS1 and rora in aMi have not previously been elucidated. The present study investigated the effect and mechanism of FGd5-aS1 and rora in human cardiomyocyte ac16 cells under hypoxia. reverse transcription-quantitative Pcr and western blotting demonstrated that FGd5-aS1 and rora were downregulated in the serum of patients with aMi and hypoxia-challenged ac16 cells. Functional experiments were performed via assays, flow cytometry and western blotting. in response to hypoxia, superoxide dismutase (Sod) activity was inhibited, but apoptosis rate and levels of reactive oxygen species and malondialdehyde were promoted in ac16 cells, accompanied by increased Bax and cleaved caspase-3 expression levels, and decreased Sod2 and glutathione peroxidase 1 expression levels. However, hypoxia-induced oxidative stress and apoptosis in ac16 cells were attenuated by ectopic expression of FGd5-aS1 or rora. Moreover, silencing rora counteracted the suppressive role of FGd5-aS1 overexpression in hypoxic injury. FGd5-aS1 controlled rora expression levels via microrna-195-5p (mir-195), as confirmed by dual-luciferase reporter and RNA pull-down assays. consistently, mir-195 knockdown suppressed hypoxia-induced oxidative stress and apoptosis in ac16 cells, which was abrogated by downregulating FGd5-aS1 or rora. in conclusion, FGd5-aS1 modulated hypoxic injury in human cardiomyocytes partially via the mir-195/rora axis, suggesting FGd5-aS1 as a potential target in interfering with the progression of aMi.

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Section: Discussionmentioning

confidence: 99%

lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195

et al. 2020

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“…While the reasons for these may yet be waiting to be discovered, extending such studies to incorporate the detection of isoform p53 proteins may offer some insight, particularly as the use of IHC can offer limitations in what type of p53 protein species can be detected (and to what extent) with absolute certainty. Nevertheless, this aspect of testing tissue samples may be starting to gain traction based on the excellent study published by Guerra et al (2016) [148], particularly as researchers look towards taking a more Integrative approach in validating the significance of the biomarkers they are assaying for [152].…”

Section: P53 and Cathepsin Expression In Tumor Samples: A Clinically mentioning

confidence: 99%

Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

Soond

Savvateeva

Макаров

et al. 2020

Cancers

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While viewed as the “guardian of the genome”, the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.

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“…25,26 Existing evidence has confirmed that stress can increase inflammatory actions in vascular and adipose tissues. 7,41 In vivo, marked increases in neutrophil and macrophage infiltration and inflammatory chemokine/cytokine expressions (i.e., monocyte chemoattractant protein-1, osteopontin, toll-like receptor, and CXCR4) and vascular aging were observed in the aortas of stressed mice, and these changes were significantly rectified by DPP-4 inhibitor anagliptin treatment ( Fig. 1).…”

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confidence: 97%

“…38 A recent study reported that individuals with and without diabetes mellitus had increased plasma DPP-4 levels and decreased plasma GLP-1 levels. 39 In mice and rats, chronic stress increased circulating and tissue DPP-4 activities and decreased plasma and brain GLP-1 levels, [40][41][42] suggesting an imbalance between GLP-1 and DPP-4 as a potential therapeutic target in the management of vascular aging and atherosclerosis in animals under experimental stress conditions.…”

mentioning

confidence: 99%

“…[58][59][60] Pharmacological inhibitions targeting GLP-1 receptor stimulation and DPP-4 activity exhibited a protective effect on the expressions and/or activities of proteolytic enzymes [e.g., cathepsin L (CatL), CatS, CatK, MMP-9, and MMP-9] and matrix protein metabolism (elastin and collagen) in the lesions of stressed animals fed a high-fat diet. 41,42,48 These therapies also suppressed the levels of plaque peroxisome proliferator-activated receptor-α (PPAR-α) and angiotensin II type 1 receptor (AT1R) proteins. 48 Both receptor systems with their ligands have been exhibited to regulate CatS/K and MMP-2/-9 expressions via the enhancement of the productions of oxidative stress and inflammatory cytokines in both of vivo and in vitro.…”

mentioning

confidence: 99%

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DPP-4/GLP-1 Axis as a Potential Therapeutic Target in Chronic Stress-related Vascular Aging and Atherosclerosis

Wan¹,

Piao²,

Nan³

et al. 2020

Preprint

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Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging, angiogenesis, and atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme (also called CD26) that acts as a membrane-anchored cell surface exopeptidase. DPP4 is upregulated in metabolic and inflammatory cardiovascular disorders. The widespread expression of DPP4 macrophages and immune cells and the noncatalytic function of DPP4 (also called CD26) as a signaling and binding protein across a wide range of species suggest a teleological role for DPP4 in inflammation and immune response. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates [e.g., stromal cell-derived factor-1α/ C-X-C chemokine receptor type-4, glucagon-like peptide-1 (GLP-1), etc.]. Over last ten year, emerging data demonstrated unexpected roles for GLP-1 and DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism,. This mini review has focuses on recent novel findings in this field, highlighting an imbalance between GLP-1 and DPP4 as a potential therapeutic molecular target in treatments of chronic psychological stress-related atherosclerotic cardiovascular disease in humans and animals.

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Dipeptidyl peptidase-4 inhibition prevents vascular aging in mice under chronic stress: Modulation of oxidative stress and inflammation

Cited by 35 publications

References 46 publications

lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195

lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195

Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

DPP-4/GLP-1 Axis as a Potential Therapeutic Target in Chronic Stress-related Vascular Aging and Atherosclerosis

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