Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

Yin, Meimei; Silljé, Herman H W; Meissner, Maxi; Gilst, Wiek H. van; Boer, Rudolf A. de

doi:10.1186/1475-2840-10-85

Cited by 108 publications

(91 citation statements)

References 39 publications

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“…The present study demonstrated that exendin-4 mitigates the hypertrophic response and prevented the deposition of collagen content, which was abrogated by depletion of MKK3 and Akt-1. However, in a long-term post-MI cardiac remodeling model, vildagliptin, an inhibitor of DPP4, produced no substantial protective effects on cardiac function or preservations in cardiac remodeling (39). This is likely due to the effects of different pharmacological agents and a different animal model.…”

Section: Discussionmentioning

confidence: 74%

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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Section: Discussionmentioning

confidence: 74%

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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“…Indeed, long-term administration of vildagliptin to normoglycemic rats both prior to and after the induction of myocardial infarction and HF did not attenuate the reduction of LVEF or modify cardiac remodeling (25). Similarly, the administration of saxagliptin to nondiabetic mice with HF secondary to cardiac-specific overexpression of Cre recombinase did not improve ventricular function or modify survival (26).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat–Fed Diabetic Mice

et al. 2015

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Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of DPP4 inhibitor–treated subjects with diabetes. We evaluated cardiovascular function in young euglycemic Dpp4−/− mice and in older, high fat–fed, diabetic C57BL/6J mice treated with either the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide or the highly selective DPP4 inhibitor MK-0626. We assessed glucose metabolism, ventricular function and remodeling, and cardiac gene expression profiles linked to inflammation and fibrosis after transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4−/− mice exhibited a cardioprotective response after TAC surgery or doxorubicin administration, with reduced fibrosis; however, cardiac mRNA analysis revealed increased expression of inflammation-related transcripts. Older, diabetic, high fat–fed mice treated with the GLP-1R agonist liraglutide exhibited preservation of cardiac function. In contrast, diabetic mice treated with MK-0626 exhibited modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins controlling inflammation and cardiac fibrosis. These findings provide a model for the analysis of mechanisms linking fibrosis, inflammation, and impaired ventricular function to DPP4 inhibition in preclinical studies.

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“…48,53 However, some studies demonstrated that prolonged availability of intact GLP-1 caused by a DPP-4 inhibitor failed to demonstrate the infarct limiting effect. [26][27][28]54 Moreover, inhibition or reduction of DPP-4 activity using DPP-4 deleted mice or pretreatment with sitagliptin before ischaemia in high fat diet-induced diabetic mice could not reduce the infarct size, but improved the survival rate by activation of cardioprotection kinase such as GSK3β, ANP and Akt. 49 These discrepant results suggest that the different animal models, the duration of ischaemia in the heart models and the minimal dose for a specific time may play a pivotal role in the reduction of the infarct size.…”

Section: Effects Of Dpp-4 Inhibitor On the Infarct Sizementioning

confidence: 99%

Cardioprotective effects of incretin during ischaemia-reperfusion

Chinda

Chattipakorn

2012

Diabetes and Vascular Disease Research

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Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP)-4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury.

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Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

Cited by 108 publications

References 39 publications

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

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

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat–Fed Diabetic Mice

Cardioprotective effects of incretin during ischaemia-reperfusion

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