DPP4 in Cardiometabolic Disease

Zhong, Jixin; Maiseyeu, Andrei; Davis, Stephen N.; Rajagopalan, Sanjay

doi:10.1161/circresaha.116.305665

Cited by 156 publications

(104 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DPP‐4 consists of a short cytoplasmic domain, a transmembrane domain, and a large extracellular domain 20. The extracellular domain contains binding sites for its ligands such as fibronectin and adenosine deaminase.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.Methods and Results IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

show abstract

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

View full text Add to dashboard Cite

show abstract

“…16,17) A DPP4 inhibitor has an anti-diabetic effect by suppressing the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastrointestinal peptide (GIP).…”

Section: -4)mentioning

confidence: 99%

“…15) Over the past few years, many researchers have shown an interest in the pleiotropic effect of the inhibition of dipeptidyl peptidase 4 (DPP4), whose activity is upregulated in a diabetic state. 16,17) A DPP4 inhibitor has an anti-diabetic effect by suppressing the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastrointestinal peptide (GIP).…”

mentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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...

show abstract

“…GLP-1 receptor (GLP-1R) agonists potentiate GLP-1R signaling, leading to increased insulin levels; reduced glucagon secretion, gastric emptying, and appetite; and modest weight loss. Dozens of preclinical studies (6,7) have demonstrated that incretin therapies reduce atherosclerosis and vascular injury, decrease inflammation, and are cardioprotective in experimental models of CVD. Furthermore, incretin therapies reduce blood pressure and decrease postprandial lipemia in subjects with type 2 diabetes and exert cardioprotective actions in short-term clinical studies (6,7).…”

mentioning

confidence: 99%

“…Dozens of preclinical studies (6,7) have demonstrated that incretin therapies reduce atherosclerosis and vascular injury, decrease inflammation, and are cardioprotective in experimental models of CVD. Furthermore, incretin therapies reduce blood pressure and decrease postprandial lipemia in subjects with type 2 diabetes and exert cardioprotective actions in short-term clinical studies (6,7). Moreover, meta-analyses of clinical trials (6,7) in subjects with diabetes without established CVD suggest that these agents may reduce cardiovascular event rates.…”

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

DPP4 in Cardiometabolic Disease

Cited by 156 publications

References 144 publications

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

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

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

Contact Info

Product

Resources

About