The GLP-1 Analogue Liraglutide Protects Cardiomyocytes from High Glucose-induced Apoptosis by Activating the Epac-1/Akt Pathway

Wu, Xiaoming; Ou, Qianying; Zhao, Wei; Liu, J.; Zhang, H.

doi:10.1055/s-0034-1384584

Cited by 21 publications

(21 citation statements)

References 30 publications

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“…5A and C), indicating that GLP-1 modulates apoptosis via other mechanisms. Interestingly, several studies on cardiac and neural tissues have demonstrated that the beneficial effects of GLP-1 on apoptosis are due to activation of the Akt pathway [33, 34]. We speculate that anti-apoptotic actions of GLP-1 may be tissue-specific.…”

Section: Discussionmentioning

confidence: 86%

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

Liao¹,

Yang²,

Liu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: GLP-1 and ghrelin are common appetite-regulating hormones. Both have multiple functions beyond metabolic regulation. However, the effects of GLP-1 and ghrelin on endothelial biology are not fully understood. Here, we investigate the roles of GLP-1 and ghrelin in microvascular endothelial apoptosis and senescence. Methods: Human microvascular endothelial cells (HMECs) were exposed to high glucose/high lipid (HG/HL) conditions and treated with GLP-1 or ghrelin. Cellular apoptosis, senescence, and mitochondrial function were measured. In addition, the MAPK and Akt signaling pathways were examined. Results: Both GLP-1 and ghrelin treatment decreased the number of TUNEL-positive cells and inhibited caspase-3 and PARP cleavage and mitochondrial dysfunction in HG/HL-exposed HMECs. GLP-1, but not ghrelin decreased the number of β-galactosidase (β-gal)-positive cells. Furthermore, GLP-1 and ghrelin inhibited ERK1/2, JNK1/2, and p38 signaling. GLP-1 suppressed Akt signaling, but ghrelin had no effect. Moreover, JNK1/2 and p38 inhibitors, but not ERK1/2 and Akt inhibitors, decreased the number of TUNEL-positive cells. Additionally, only the Akt inhibitor decreased the number of β-gal-positive cells. Conclusion: These results demonstrate that GLP-1 and ghrelin inhibit mitochondrial dysfunction under HG/HL conditions, and suppress endothelial apoptosis via inhibiting JNK1/2 and p38 signaling; moreover, GLP-1 alleviates endothelial senescence via inactivating Akt signaling.

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Section: Discussionmentioning

confidence: 86%

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

Liao¹,

Yang²,

Liu³

et al. 2017

Cell Physiol Biochem

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“…In a previous study, we found a significant increase (p < 0.01) in the expression of pAkt (Ser473) in the Liraglutide pre-treated SH-SY5Y cells, stressed with methyl glyoxal (Sharma et al 2014). One study testing Liraglutide showed that it protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway (Wu et al 2014). Research on Exendin-4 treatment revealed elevated phosphorylation of the prosurvival kinase Akt (Robinson et al 2015) and its potential involvement in protecting pancreatic beta cells from human islet amyloid polypeptide-induced cell damage (Fan et al 2010).…”

Section: Discussionmentioning

confidence: 93%

“…One study testing Liraglutide showed that it protects cardiomyocytes from high glucose‐induced apoptosis by activating the Epac‐1/Akt pathway (Wu et al . ). Research on Exendin‐4 treatment revealed elevated phosphorylation of the pro‐survival kinase Akt (Robinson et al .…”

Section: Discussionmentioning

confidence: 97%

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Jalewa

Sharma

Hölscher

2016

Journal of Neurochemistry

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Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 μM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 μM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells treated with the stressor Rotenone. The novel GLP-1/GIP dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. The drugs protected the cells from rotenone-induced impairment in cell growth and Akt activation, mitochondrial damage, impairments of autophagy and apoptotic cell signalling. See paper for details.

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“…Thereafter, sitagliptin improved LV systolic dysfunction. An GLP-1 analog protected cardiomyocytes against high glucose-induced apoptosis by activating the Epac-1/Akt pathway (35). However, the exact mechanism of sitagliptin reversing these changes and the signal pathway remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Sitagliptin alleviated myocardial remodeling of the left ventricle and improved cardiac diastolic dysfunction in diabetic rats

Liu

Huang

Wang

et al. 2015

Journal of Pharmacological Sciences

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The GLP-1 Analogue Liraglutide Protects Cardiomyocytes from High Glucose-induced Apoptosis by Activating the Epac-1/Akt Pathway

Abstract: Liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway.

Cited by 21 publications

References 30 publications

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Sitagliptin alleviated myocardial remodeling of the left ventricle and improved cardiac diastolic dysfunction in diabetic rats

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