Glucagon-Like Peptide-1 Receptor Agonist Attenuates Autophagy to Ameliorate Pulmonary Arterial Hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3β Pathways

Wu, Yi-Chia; Wang, Wei‐Ting; Lee, Su-Shin; Kuo, Yur‐Ren; Wang, Ya-Chin; Yen, Shih‐Jung; Lee, Mei‐Yueh; Yeh, Jwu‐Lai

doi:10.3390/ijms20143435

Cited by 45 publications

(31 citation statements)

References 47 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As demonstrated in animal studies and experiments using human cells, GLP-1 receptors expressed in endothelial cells, monocytes, macrophages, and vascular smooth muscle cells produce numerous effects potentially interfering with the process of atherosclerotic plaque formation or rupture. First, ROS production is reduced by GLP-1 [ [128] , [129] , [130] ], exenatide [ 131 ], liraglutide [ 130 , [132] , [133] , [134] , [135] , [136] ], and semaglutide [ 137 ]. The oxLDL-mediated activation of monocytes and macrophages and the consecutive activation of adhesion molecules such as VCAM-1, MCP-1, E-selectin, and ICAM-1 is successfully reduced by GLP-1 receptor stimulation (e.g., GLP-1 [ 138 ], exenatide [ [138] , [139] , [140] ], dulaglutide [ 141 ], and liraglutide [ 142 ]).…”

Section: Cardiovascular Outcome Studiesmentioning

confidence: 99%

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Nauck

Quast

Wefers

2021

Molecular Metabolism

621

570

View full text Add to dashboard Cite

Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA 1c , both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA 1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal comp...

show abstract

Section: Cardiovascular Outcome Studiesmentioning

confidence: 99%

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Nauck

Quast

Wefers

2021

Molecular Metabolism

621

570

View full text Add to dashboard Cite

show abstract

“…It has been reported in the literature that autophagy is related to the pathophysiological process of many diseases, such as cancer, metabolic and neurodegenerative diseases, and cardiovascular and pulmonary diseases. 31,32 Therefore, it is vital to study the role of autophagy in OSF. Overexpression of autophagy marker LC3 has been observed in the tissue samples of OSF patients, and many studies have shown that pro-fibrotic cytokines (IL-1, IL-6, TGF-β, PDGF, bFGF, and IGF) promote collagen synthesis.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor Regulates the Biological Behavior of Oral Mucosal Fibroblasts by Inducing Cell Autophagy and Its Mechanism

Wang¹,

Yang²,

You³

et al. 2021

JIR

View full text Add to dashboard Cite

Objective: To explore the effect of platelet-derived growth factor (PDGF) on oral mucosal fibroblast autophagy and further elucidate the molecular mechanism by which PDGF-BB regulates the biological behavior of oral mucosal fibroblasts by inducing autophagy. Methods: Primary oral mucosal fibroblasts were isolated and cultured by the tissue block and trypsin methods and identified by indirect immunofluorescence vimentin detection. We detected the autophagy marker Beclin-1 and fibrosis marker Col-I of the primary oral mucosal fibroblasts at different time points after stimulating the fibroblasts with different PDGF-BB concentrations by Western blotting and determined the best experimental concentration and stimulation time of PDGF-BB. Then, indirect immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction (PCR) were used to detect the effect of PDGF-BB on the expression of autophagy-related and fibrotic proteins before and after 3-methyladenine (3-MA) intervention. Additionally, the effect of 3-MA on the proliferation and migration of primary oral mucosal fibroblasts stimulated by PDGF-BB was detected by the MTT method and a scratch experiment. The effect of PDGF-BB on Beclin-1 and phosphatidylinositol-3 kinase class 3 (PI3KC3) interaction was detected by coimmunoprecipitation. Results:The results demonstrated that PDGF-BB could induce autophagy of the oral mucosal fibroblasts, showing a certain time and dose correlation. It induced cell autophagy through Beclin-1 and PI3KC3 interaction to promote the proliferation, migration, conversion, and collagen synthesis of the fibroblasts. However, 3-MA inhibited the combination of Beclin-1 and PI3KC3 and weakened the fibroblasts' proliferation, migration, conversion, and collagen synthesis activities. Conclusion: Overall, PDGF-BB induces autophagy through the Beclin-1 pathway to regulate the biological behavior of oral mucosal fibroblasts.

show abstract

“…GLP-1 receptor stimulation appears to attenuate these processes in preclinical models and human studies in various ways. GLP-1 receptor stimulation (e.g., through GLP-1 ( 24 – 27 ), exenatide ( 28 ), liraglutide ( 26 , 29 – 32 ), or semaglutide ( 33 ) prevents ROS and reduces vascular oxidative stress. The secretion of adhesion molecules including VCAM-1, MCP-1, ICAM-1, and E-selectin is also reduced by GLP-1 ( 34 ), exenatide ( 34 – 36 ), liraglutide ( 37 ), and dulaglutide ( 22 ).…”

Section: Mechanisms For the Cardiovascular Benefits Of Glp-1rasmentioning

confidence: 99%

Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6

Nauck

2021

Front. Endocrinol.

View full text Add to dashboard Cite

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58–0.95) and 0.79 (0.57–1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

show abstract

Glucagon-Like Peptide-1 Receptor Agonist Attenuates Autophagy to Ameliorate Pulmonary Arterial Hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3β Pathways

Cited by 45 publications

References 47 publications

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Platelet-Derived Growth Factor Regulates the Biological Behavior of Oral Mucosal Fibroblasts by Inducing Cell Autophagy and Its Mechanism

Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6

Contact Info

Product

Resources

About