A Glucagon-Like Peptide-1 Analog Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity

Noyan-Ashraf, Mohammad Hossein; Shikatani, Eric A.; Schuiki, Irmgard; Mukovozov, Ilya; Wu, Jun; Li, Ren‐Ke; Volchuk, Allen; Robinson, Lisa A.; Billia, Filio; Drucker, Daniel J.; Husain, Mansoor

doi:10.1161/circulationaha.112.091215

Cited by 209 publications

(191 citation statements)

References 52 publications

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“…8) Liraglutide, a glucagon-like peptide-1 analogue, has been found to inhibit oxidative stress and inflammatory response in the endothelial cells, heart and brain. 19,20,22,23) Results obtained from the present study contribute to further understanding of the mechanisms whereby liraglutide exerts a protective effect against high fat and high cholesterol diet induced hepatic steatosis, insulin resistance and liver dysfunction. Administration of liraglutide effectively alleviated hepatic oxidative stress and inflammatory response.…”

Section: Discussionmentioning

confidence: 62%

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The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

Gao

Zeng

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been demonstrated to reduce hepatic steatosis. However, the mechanism of the lipid-lowering effect of liraglutide in the liver remains unclear. The aim of the present study was to investigate the beneficial effect of liraglutide on diet-induced non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism in rats. NAFLD was induced in Sprague-Dawley rats by feeding a high fat and high cholesterol (HFHC) diet. Liraglutide (0.6 mg/kg body weight/d) was injected intraperitoneally to the rats subjected to HFHC diet four weeks before sacrificing the animals. Body and liver weight, fasting blood glucose (FBG), fasting insulin, serum aminotransferase (ALT) and lipid accumulation in the liver were determined. Markers of oxidative stress, such as malondialdehyde (MDA), free fatty acid (FFAs), superoxide dismutase (SOD), and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) were detected by colorimetric detection or enzyme-linked immunosorbent assay (ELISA). Serum and hepatic adiponectin were measured by ELISA. The expression of c-Jun N-terminal kinase-1 (JNK-1) and phosphorylated JNK-1 were examined by Western blotting. Liraglutide improved insulin resistance, decreased hepatic steatosis and reversed liver dysfunction. The hepatic levels of MDA, FFAs, and TNF-α were significantly decreased versus controls. Meanwhile, administration of liraglutide significantly increased SOD and adiponectin levels in the liver and inhibited the expression of JNK-1 and phosphorylated JNK-1 versus control rats. Liraglutide exerted anti-oxidative and anti-inflammatory effects in the liver and consequently reversed hepatic steatosis and insulin resistance. Such effects might be mediated by the elevation of adiponectin levels and the inactivation of JNK-1.

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Section: Discussionmentioning

confidence: 62%

“…21) In addition, the anti-inflammatory effect of liraglutide has been demonstrated in the heart of mice with diabetes and the brain of mice with Alzheimer's disease. 22,23) We have previously published preliminary data of the hepatic effect of GLP-1 on oxidative stress and inflammatory factors.…”

mentioning

confidence: 99%

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

Gao

Zeng

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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“…First, 3.8 mg of liraglutide was dissolved in 0.5 mL of a 1% (w/v) aqueous sodium acetate solution with 2% PVA, and 25 mg of PLGA-PEG was dissolved in 2.5 mL of dichloromethane (DCM). 22 The solution was then emulsified by sonication on ice in 12.5 mL of a 2% PVA solution using a probe sonicator. Then, the emulsion was stirred at 550 rpm for 3 h to evaporate the solvent.…”

mentioning

confidence: 99%

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Qi¹,

Lü

Li³

et al. 2017

IJN

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The local, intramyocardial injection of proteins into the infarcted heart is an attractive option to initiate cardiac regeneration after myocardial infarction (MI). Liraglutide, which was developed as a treatment for type 2 diabetes, has been implicated as one of the most promising protein candidates in cardiac regeneration. A significant challenge to the therapeutic use of this protein is its short half-life in vivo. In this study, we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic- co -glycolic acid)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (NP-liraglutide) on experimental MI. PLGA–PEG nanoparticles (NPs) have been shown to efficiently load liraglutide and release bioactive liraglutide in a sustained manner. For in vitro test, the released liraglutide retained bioactivity, as measured by its ability to activate liraglutide signaling pathways. Next, we compared the effects of an intramyocardial injection of saline, empty NPs, free liraglutide and NP-liraglutide in a rat model of MI. NPs were detected in the myocardium for up to 4 weeks. More importantly, an intramyocardial injection of NP-liraglutide was sufficient to improve cardiac function ( P <0.05), attenuate the infarct size ( P <0.05), preserve wall thickness ( P <0.05), promote angiogenesis ( P <0.05) and prevent cardiomyocyte apoptosis ( P <0.05) at 4 weeks after injection without affecting glucose levels. The local, controlled, intramyocardial delivery of NP-liraglutide represents an effective and promising strategy for the treatment of MI.

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“…Contrary to this work, studies of Dai et al (2013) showed that liraglutide inhibit nuclear factor kappa B (NF-κB) phosphorylation that culminates in suppression of ET-1 expression. However, it was found that liraglutide (30 µg/kg twice daily) reversed insulin resistance, obesity-induced perturbations in cardiac endothelial nitric oxide synthase in high fat diet mice (Noyan-Ashraf et al, 2013).…”

Section: Discussionmentioning

confidence: 98%

Impact of liraglutide versus atorvastatin on cardiovascular changes in rat model of adenine induced chronic renal failure

Shata¹,

Elmorsy²,

Elesawy³

et al. 2017

Afr. J. Pharm. Pharmacol.

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The prevalence of cardiovascular changes markedly increases with deterioration of patient's renal function and can stack up 65 to 70% in end-stage renal disease. A rapid fall in renal function is often associated with uncontrolled congestive heart failure. Beyond their lipid-lowering effect, statins have been shown to protect the heart in different diseases. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue, used to control diabetes. It improves cardiac dysfunction in non-diabetics, but underlying mechanisms remain to some extent, unclear. Fifty two male Sprague-Dawley rats weighing 200 to 250 g were grouped into negative control, positive control, liraglutide treated group (0.3 mg/kg), atorvastatin treated group (10 mg/kg), liraglutide and atorvastatin treated group (0.3 and 10 mg/kg, respectively), liraglutide and atorvastatin treated group (0.15 and 5 mg/kg, respectively). Combination of both drugs significantly reduce creatine phosphokinase isoenzyme (CK-MB) in both doses (p<0.008, p <0.002) and lactate dehydrognase (LDH) (p<0.04, p<0.01). Liraglutide alone or in combination with atorvastatin in both doses (p<0.02, p<0.01 and p<0.01) significantly increased superoxide dismutase (SOD). Atorvastatin alone (p<0.02) or in combination with liraglutide in both doses (p<0.001, p<0.001) induced a significant decrease of malondialdehyde (MDA). Atorvastatin alone (p<0.01) or in combination with liraglutide in both doses induced a significant amelioration of nitric oxide (NO) and cholesterol (p<0.01 and p<0.02). Significant improvements in blood urea nitrogen (BUN) and glucose profile were seen with all tested drugs either single or in combination. Combined implementation of both drugs improves histopathological changes of cardiac muscle fibres. Liraglutide has promising effects on cardiovascular changes in adenine induced chronic nephropathy through modulation of LDH, CK-MB and improvement of NO and SOD. Also, it can mitigate fibrosis and cardiac tissue changes. Its effects markedly increase in conjunction with atorvastatin. Combined administration of liraglutide and atorvastatin in a high dose has a reliable effect on improving outcome in biochemical and histopthological cardiac muscle fibers changes.

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A Glucagon-Like Peptide-1 Analog Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity

Cited by 209 publications

References 52 publications

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Impact of liraglutide versus atorvastatin on cardiovascular changes in rat model of adenine induced chronic renal failure

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