GLP-1 and cardioprotection: from bench to bedside

Ravassa, Susana; Zudaire, Amaia; Dı́ez, Javier

doi:10.1093/cvr/cvs123

Cited by 104 publications

(90 citation statements)

References 80 publications

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“…For example, GLP-1 treatment, either GLP-1 agonist or DPP-4 inhibitors, limits ischemic injury in perfused hearts in intact animals (8,34,52) as well as in cardiomyocytes (33). The data suggest that the phosphoinositide 3-kinase-Akt pathway is involved in this protective effect of GLP-1.…”

Section: Discussionmentioning

confidence: 91%

“…It acts through a G-coupled receptor (GLP-1R), which is present on pancreatic ␤-cells, where it displays glucoregulatory and insulinotropic effects. This receptor is also expressed in other cell types, including cardiomyocytes, and several GLP-1 cardiovascular beneficial properties have been attributed to a direct effect of GLP-1 on heart, in animal models as well as in humans (34).…”

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confidence: 99%

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AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes

Balteau¹,

Steenbergen²,

Timmermans³

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

105

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Exposure of cardiomyocytes to high glucose concentrations (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase (NOX2). NOX2 activation is triggered by enhanced glucose transport through a sodium-glucose cotransporter (SGLT) but not by a stimulation of glucose metabolism. The aim of this work was to identify potential therapeutic approaches to counteract this glucotoxicity. In cultured adult rat cardiomyocytes incubated with 21 mM glucose (HG), AMP-activated protein kinase (AMPK) activation by A769662 or phenformin nearly suppressed ROS production. Interestingly, glucagon-like peptide 1 (GLP-1), a new antidiabetic drug, concomitantly induced AMPK activation and prevented the HG-mediated ROS production (maximal effect at 100 nM). α2-AMPK, the major isoform expressed in cardiomyocytes (but not α1-AMPK), was activated in response to GLP-1. Anti-ROS properties of AMPK activators were not related to changes in glucose uptake or glycolysis. Using in situ proximity ligation assay, we demonstrated that AMPK activation prevented the HG-induced p47phox translocation to caveolae, whatever the AMPK activators used. NOX2 activation by either α-methyl-d-glucopyranoside, a glucose analog transported through SGLT, or angiotensin II was also counteracted by GLP-1. The crucial role of AMPK in limiting HG-mediated NOX2 activation was demonstrated by overexpressing a constitutively active form of α2-AMPK using adenoviral infection. This overexpression prevented NOX2 activation in response to HG, whereas GLP-1 lost its protective action in α2-AMPK-deficient mouse cardiomyocytes. Under HG, the GLP-1/AMPK pathway inhibited PKC-β2 phosphorylation, a key element mediating p47phox translocation. In conclusion, GLP-1 induces α2-AMPK activation and blocks HG-induced p47phox translocation to the plasma membrane, thereby preventing glucotoxicity.

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes

Balteau¹,

Steenbergen²,

Timmermans³

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

105

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“…Antiapoptosis is regarded as one of the most important cytoprotections among the pleiotropic actions reported for GLP-1 (17,27). Exendin-4 treatment resulted in a decrease in cleaved PARP and active caspase-3; these decreases were abrogated by deletion of MKK3 and Akt-1.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

Zhang

Wang

et al. 2016

American Journal of Physiology-Cell Physiology

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-We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI ϩ exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1 Ϫ/Ϫ ;MKK3 Ϫ/Ϫ mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3 Ϫ/Ϫ , Akt-1 Ϫ/Ϫ , and Akt-1 Ϫ/Ϫ ; MKK3 Ϫ/Ϫ mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway.glucagon-like peptide-1 receptor; MAPK kinase 3; Akt-1; myocardial infarction; function GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is a naturally occurring incretin that is implicated in the control of appetite and satiety (23). GLP-1 has been studied extensively in type 2 diabetes as a novel insulinotropic peptide whose actions are dependent on the ambient glucose concentration. GLP-1 acts through the GLP-1 receptor (GLP-1R), a 463-amino acid member of the G protein-coupled receptor superfamily (23). GLP-1 is rapidly cleaved by dipeptidyl-peptidase-4 (DPP4), which results in the generation of largely inactive molecular GLP-1 9 -36 amide and GLP-1 9 -37 forms (14). The majority of GLP-1 leaving the intestinal venous circulation has already been cleaved by DPP4 expressed in capillary surrounding gut L cells, which provides an estimated half-life of 1-2 min for intact GLP-1 in vivo (12). The GLP-1 receptor is widely distributed in tissues, including brain, pancreas, intestine, lung, stomach, and kidney. Recently, multiple GLP-1 receptor agonists with longer duration of effect in vivo have been explored, among which is exendin-4, a 39-amino acid peptide that shares 53% sequence ho...

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“…Therefore, GLP-1 analogs and DPP4 inhibitors are commonly prescribed for the treatment of diabetes mellitus (6,11). DPP4 inhibitors also exert extrapancreatic effects in the brain, stomach, and heart (39). However, the mechanisms by which they mediate these effects remain largely unknown.…”

mentioning

confidence: 99%

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

Ihara

Asanuma

Yamazaki

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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zuki N, Kitakaze M. An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 308: H1287-H1297, 2015. First published March 7, 2015; doi:10.1152/ajpheart.00835.2014.-Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1-and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 Ϯ 2.5% to 17.1 Ϯ 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3␤, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor-and CREB-dependent signaling pathways. dipeptidyl peptidase 4 inhibitor; ischemia-reperfusion injury; myocardial infarction; cardioprotection; adenosine GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is mostly known as a potent antihyperglycemic hormone secreted by intestinal cells to stimulate glucose-dependent insulin secretion from pancreatic beta cells. Once in circulation, GLP-1 is rapidly metabolized by dipeptidyl peptidase 4 (DPP4). Therefore, GLP-1 analogs and DPP4 inhibitors are commonly prescribed for the treatment of diabetes mellitus (6, 11). DPP4 inhibitors also exert extrapancreatic effects in the brain, stomach, and heart (39). However, the mechanisms by which they mediate these effects remain largely unknown. Several reports showed that DPP4 inhibitors limit the infarct size after ischemia-reperfusion in the heart (15, 51), but the extent of their beneficial effects remains controversial (7,52). Recently, several reports have indicated that DPP4 forms a complex with adenosin...

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GLP-1 and cardioprotection: from bench to bedside

Cited by 104 publications

References 80 publications

AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes

AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes

Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

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