Genetic Deletion or Pharmacological Inhibition of Dipeptidyl Peptidase-4 Improves Cardiovascular Outcomes After Myocardial Infarction in Mice

Sauvé, Meghan; Ban, Kiwon; Momen, M. Abdul; Zhou, Yuqing; Henkelman, R. Mark; Husain, Mansoor; Drucker, Daniel J.

doi:10.2337/db09-0955

Cited by 248 publications

(199 citation statements)

References 47 publications

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“…Taken together, similar trends with TG mice were observed in non-DM WT, WT-DM, and WT-DM-DPP4 inhibition groups, but these levels were low, and thus did not lead to decrease in infarct size in WT mice. Sauve et al reported that infarct size in genetic DPP4 deletion mice did not differ with that in WT mice, 37) and their data were consistent with our present study. In addition, Shigeta, et al reported that VEGF expression in cardiac muscle tissue was suppressed in the diabetic state with inhibition of DPP4 activity in a chronic heart failure model induced by transaortic constriction.…”

Section: Discussionsupporting

confidence: 83%

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

et al. 2017

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SummaryHigh mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, promotes angiogenesis and tissue repair, resulting in restored cardiac function after myocardial infarction (MI). Although dipeptidyl peptidase 4 (DPP4) degrades certain peptides, it remains unclear as to whether HMGB1 is a substrate of DPP4 and whether DPP4 inhibition prevents the cleavage of HMGB1.In transgenic mice with cardiac-specific overexpression of HMGB1 (TG) and wild-type mice (WT), a diabetic state was induced by streptozotocin, and MI was created by ligation of the left anterior descending coronary artery. To inhibit DPP4 activity, a DPP4 inhibitor anagliptin was used. The plasma levels of HMGB1, infarct size, echocardiographic data, angiogenesis, and vascular endothelial growth factor (VEGF) expression in the peri-infarct area were compared among non-diabetic MI WT/TG, diabetic MI WT/TG, and anagliptin-treated diabetic MI WT/TG mice.DPP4 activity was increased in the diabetic state and blocked by anagliptin administration. The HMGB1 plasma levels were reduced in the diabetic TG compared with the non-diabetic TG mice, but DPP4 inhibition with anagliptin increased HMGB1 plasma levels in the diabetic TG mice. The infarct area was significantly larger in the diabetic TG than in the non-diabetic TG mice, and it was reduced by DPP4 inhibition. Cardiac function, angiogenesis, and VEGF expression were impaired in the diabetic TG mice, but they were ameliorated by the DPP4 inhibition to levels similar to those found in the non-diabetic TG mice.The DPP4 inhibitor ameliorated cardiac function by inhibiting the inactivation of HMGB1 in diabetic mice after MI.(Int Heart J 2017; 58: 778-786) Key words: Angiogenesis, Ischemic heart disease, Diabetes mellitus A cute myocardial infarction (MI) is an emergent disease caused by occlusion of the coronary artery. The morbidity and mortality of MI remain high despite the advancement of emergency medical services and the development of optimal therapies, including pharmacological treatment and percutaneous coronary intervention, and surgical technique. 1) Infarct size is known as an important prognostic predictor; thus, many studies of ischemic heart disease have been performed to determine how to limit the extent of infarction, focusing on the mechanisms of collateral development, ischemic reperfusion injury and ischemic preconditioning, among others. 2-4)High mobility group box 1 (HMGB1) is a ubiquitous non-histone DNA-binding protein that mediates gene transcription.5-7) HMGB1 secreted from necrotic cells into the extracellular space triggers tissue repair as a cytokine. [8][9][10][11] Moreover, several studies have proven that HMGB1 is involved in limiting the size of the infarct area and preserving cardiac function by promoting angiogenesis. 12,13) In addition, we have previously demonstrated that HMGB1 promotes angiogenesis and tissue repair by enhancing mobilization and differentiation of endothelial progenitor cells from bone marrow, resulting in preserving cardiac function after MI.14) Th...

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Section: Discussionsupporting

confidence: 83%

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

et al. 2017

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“…Four weeks after the induction of MI by coronary ligation, the infarcted rat hearts were isolated and subjected to no treatment (vehicle), sitagliptin (5 μM), GIP (100 nM), GLP-1 (100 nM), or the combination of sitagliptin and GIP. The doses of sitagliptin, GIP and GLP-1 have been shown to be effective in modulating biological activities [25,26]. Noncirculating modified Tyrode's solution was used to perfuse each heart, containing glucose 5.5 mM, NaCl 117.0 mM, NaHCO 3 23.0 mM, KCl 4.6 mM, NaH 2 PO 4 0.8 mM, MgCl 2 1.0 mM and CaCl 2 2.0 mM, equilibrated at 37 • C with a 95 % O 2 and 5 % CO 2 gas mixture.…”

Section: Experiments 2 (Ex Vivo)mentioning

confidence: 99%

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

2016

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SynopsisMyocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptintreated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.

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“…Dpp4 2/2 mice (Supplementary Fig. 1) were described previously (12); for doxorubicin experiments, n = 4-12 mice per group for vehicle controls and 9-12 mice per group for doxorubicin treatment. For TAC studies in Dpp4 +/+ vs. Dpp4 2/2 vs. mice, n = 6-7 per group.…”

Section: Animals Reagents and Dietsmentioning

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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Genetic Deletion or Pharmacological Inhibition of Dipeptidyl Peptidase-4 Improves Cardiovascular Outcomes After Myocardial Infarction in Mice

Cited by 248 publications

References 47 publications

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

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

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