Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice

Chen, Peng; Yang, Fen; Wang, Wenya; Li, Xiao; Liu, Dongling; Zhang, Yongxi; Yin, Guotian; Lv, Fenghua; Guo, Zhikun; Mehta, J. L.; Wang, Xianwei

doi:10.1177/1074248420942007

Cited by 22 publications

(19 citation statements)

References 47 publications

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“…The link between CF proliferation and AF is now universally recognized, and overproliferation of CFs contributes to the increase of dysfunctional extracellular matrix (ECM) (26). In the present study, human CFs were treated with AngII to establish a cell model of AF as previously reported (19). Consistent with the results observed in clinical samples, high expression of TUG1 was also detected in the AF cell models.…”

Section: Discussionsupporting

confidence: 83%

“…The human cardiac fibroblasts (HCFs) were provided by ScienCell Research Laboratory (San Diego, CA). All cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS; Invitrogen Life Technologies, Carlsbad, CA, USA) and penicillin-streptomycin solution in an incubator with 5% CO 2 and 95% air at 37 • C. The HAFs were treated with 10 −7 mol/L angiotensin II (AngII; Sigma-Aldrich, St. Louis, MO, USA) for 24 h to establish a cell model of AF as previously reported (19).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

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LncRNA TUG1 Regulates Proliferation of Cardiac Fibroblast via the miR-29b-3p/TGF-β1 Axis

Guo

Sun

Chen

et al. 2021

Front. Cardiovasc. Med.

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Background: Atrial fibrillation (AF) is a very common clinical arrhythmia, accompanied by the overproliferation of cardiac fibroblasts (CFs). This study aimed to investigate the role of the long non-coding RNA(lncRNA) taurine upregulated gene 1 (TUG1) in the proliferation of CFs and further investigated its underlying mechanism.Methods: One hundred four paroxysmal AF patients and 94 healthy controls were recruited. Human cardiac fibroblasts (HCFs) were applied to establish an AF cell model through treatment with angiotensin II (AngII). qRT-PCR was used for the measurement of gene levels. The cell proliferation was detected by cell counting kit-8 (CCK-8). Luciferase reporter assay was performed for target gene analysis.Results: Elevated levels of TUG1 and low expression of miR-29b-3p were detected in the serum of AF patients compared with the healthy controls. Pearson's correlation analysis exhibited an inverse relationship between TUG1 and miR-29b-3p expression in AF patients (r = −7.106, p < 0.001). Knockdown of TUG1 inhibited AngII-induced CF proliferation. Taurine upregulated gene 1 (TUG1) functions as a competing endogenous RNA (ceRNA) for miR-29b-3p, and downregulation of miR-29b-3p reversed the role of TUG1 in CF proliferation. TGF-β1 is a direct target gene of miR-29b-3p.Conclusions: Long non-coding RNA taurine upregulated gene 1 is a key regulator in the occurrence of AF. Slicing TUG1 inhibits CF proliferation by regulating the miR-29b-3p/TGF-β1 axis.

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Section: Discussionsupporting

confidence: 83%

Section: Cell Culture and Treatmentmentioning

confidence: 99%

LncRNA TUG1 Regulates Proliferation of Cardiac Fibroblast via the miR-29b-3p/TGF-β1 Axis

Guo

Sun

Chen

et al. 2021

Front. Cardiovasc. Med.

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“…Cardiac fibrosis is a chronic process characterized by abnormal collagen accumulation, resulting in myocardium stiffening, reduced contractility, impaired cardiac function and clinical heart failure ( 16 , 17 ). It is known that aging is an independent risk factor for cardiac fibrosis in the elderly ( 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that aging-dependent stimulation to RAS in myocardium induces an increase of NADPH oxidase activity, promotes ROS production, and activates transforming growth factor-β (TGF-β) signaling, which leads to pathological myocardial fibrosis ( 22 , 23 ). Ang II stimulates collagen synthesis in fibroblasts through activating AT1R ( 17 ). In this study, we also observed that cardiac fibrosis and collagen accumulation were markedly enhanced in the hearts of the aged mice given Ang II for 4 weeks ( Figures 5 , 6 ).…”

Section: Discussionmentioning

confidence: 99%

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension

Tang

Liu

et al. 2021

Front. Cardiovasc. Med.

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Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a transmembrane glycoprotein that mediates uptake of oxidized low-density lipoprotein (ox-LDL) into cells. Previous studies had shown that LOX-1 deletion had a potential to inhibit cardiac fibrosis in mouse models of hypertension and myocardial infarction. Whether LOX-1 deletion also affects cardiac fibrosis associated with aging still remains unknown. The aim of this study was to investigate the effect of LOX-1 deletion on myocardial fibrosis in the aged mice.Methods: C57BL/6 mice and LOX-1 knockout (KO) mice with C57BL/6 background were studied to the age of 60 weeks. Both genotypes of aged mice were exposed to angiotensin II (Ang II) or saline for additional 4 weeks. The mice were then sacrificed, and myocardial fibrosis, reactive oxygen species (ROS) and expression of LOX-1, fibronectin, collagens, p22phox, and gp91phox were measured.Results: LOX-1 deletion markedly reduced Ang II-mediated rise of blood pressure in the aged mice (vs. saline-treated mice). LOX-1 deletion also limited fibrosis and decreased fibronectin and collagen-3 expression in the hearts of aged mice, but not the expression of collagen-1 and collagen-4. LOX-1 deletion also inhibited ROS production and p22phox expression. As the aged mice were exposed to Ang II for 4 weeks (resulting in hypertension), LOX-1 deletion more pronounced inhibiting myocardial fibrosis and ROS production, and decreasing expression of fibronectin, collagen-1, collagen-2, collagen-3, p22phox, and gp91phox.Conclusion: LOX-1 deletion limited fibrosis and ROS production in the hearts of aged mice. This effect was more pronounced in the aged mice with hypertension induced by Ang II infusion.

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“…In addition to regulating cardiomyocyte function, GLP-1RAs also improve the function of cardiac fibroblasts. For example, GLP-1RAs may modulate the CD36-JNK-AP1 pathway by partially down-regulating prolyl 4-hydroxylase subunit alpha-1 (P4HA1), and then inhibit ROS production mediated by Ang II type I receptor, thereby ameliorating cardiac fibroblast proliferation and myocardial fibrosis [167,168]. Furthermore, as for cardiac fibroblasts, GLP-1RAs inhibit Ang II and glucose-induced collagen formation via decreasing phospho-NF-κB-p65 and phospho-ERK1/2 expression [169] (Figure 2).…”

Section: Improving Cardiomyocyte/cardiac Fibroblast Dysfunction By Glp-1rasmentioning

confidence: 99%

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

Ma¹,

Liu²,

Ilyas³

et al. 2021

Int. J. Biol. Sci.

131

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Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.

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Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice

Cited by 22 publications

References 47 publications

LncRNA TUG1 Regulates Proliferation of Cardiac Fibroblast via the miR-29b-3p/TGF-β1 Axis

LncRNA TUG1 Regulates Proliferation of Cardiac Fibroblast via the miR-29b-3p/TGF-β1 Axis

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

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