The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype

Vinué, Ángela; Navarro, Jorge; Herrero-Cervera, Andrea; García-Cubas, Marta; Andrés‐Blasco, Irene; Martínez-Hervás, Sergio; Real, José T.; Ascaso, Juan F.; González-Navarro, Herminia

doi:10.1007/s00125-017-4330-3

Cited by 94 publications

(58 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In our study ApoE −/− mice received a single daily dose of 300 μg/kg liraglutide for 6 weeks resulting in significant reduction of lesion progression at the iliac bifurcation of the aorta. Previous in vivo studies administered liraglutide for 4 weeks [ 30 – 32 , 35 ]. 300 μg/kg liraglutide has previously shown to have little effect on weight loss [ 24 , 36 ] meaning the atheroprotective effects we report are weight-independent.…”

Section: Discussionmentioning

confidence: 99%

“…However, few studies have addressed the effect of liraglutide on the inflammatory status of monocytes and macrophages in vivo in the context of atherosclerosis. Most recently Vinué et al reported that lixisenatide decreases atherosclerosis in insulin resistant mice by reprogramming macrophages towards an MΦ2 phenotype [ 35 ]. Indeed, our initial approach using THP-1 monocytes suggested that liraglutide influences monocyte/macrophage cell fate.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

Bruen

Curley

Kajani

et al. 2017

Cardiovasc Diabetol

View full text Add to dashboard Cite

BackgroundMacrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response.MethodsHuman THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE−/−) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE−/− mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 μg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MΦ1 and MΦ2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE−/− mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry.ResultsLiraglutide decreased atherosclerotic lesion formation in ApoE−/− mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MΦ0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MΦ2 surface marker mannose receptor in both MΦ0 and MΦ2 macrophages. Significant reduction in total lesion development was found with once daily 300 μg/kg liraglutide treatment in ApoE−/− mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MΦ1 markers (CCR7, IL-6 and TNF-alpha), augmented MΦ2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MΦ1-like monocytes and macrophages from bone marrow-derived cells.ConclusionsThis data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MΦ2 pro-resolving macrophages.Electronic supplementary materialThe online version of this article (10.1186/s12933-017-0626-3) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

Bruen

Curley

Kajani

et al. 2017

Cardiovasc Diabetol

View full text Add to dashboard Cite

show abstract

“…Numerous studies have demonstrated that signalling through the GLP‐1 receptor has direct effects to inhibit the formation and promote the stability of atheromatous plaques. In experimental models, GLP‐1 receptor agonists reduce the infiltration of macrophages, promote thicker fibrous caps and minimize smooth muscle proliferation . The net effect of these actions is a slowing of the atherosclerotic process, an attenuation of the inflammatory response in blood vessels, and a reduction in the likelihood of plaque rupture.…”

Section: Interplay Of Glucagon‐like Peptide‐1 Signalling and Neprilysmentioning

confidence: 99%

Augmentation of glucagon‐like peptide‐1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure

Packer

2018

European J of Heart Fail

View full text Add to dashboard Cite

Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

show abstract

“…In addition, signalling through the GLP-1 receptor may have direct effects of inhibiting atheroma formation and promoting plaque stability [24,25], which may underlie the ability of long-acting receptor agonists to reduce the occurrence of thromboembolic events ( Fig. 1) [11][12][13].…”

Section: Contrasting Macrovascular Effects Of Natriuretic Anti-hypergmentioning

confidence: 99%

Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure

Packer

2018

Diabet. Med.

View full text Add to dashboard Cite

Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.

show abstract

The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype

Cited by 94 publications

References 40 publications

Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

Augmentation of glucagon‐like peptide‐1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure

Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure

Contact Info

Product

Resources

About