DPP-4 inhibition has beneficial effects on the heart after myocardial infarction

Kubota, Akihiko; Takano, Hiroyuki; Wang, Haixiu; Hasegawa, Hiroshi; Tadokoro, Hiroyuki; Hirose, Masao; Kobara, Yuka; Yamada-Inagawa, Tomoko; Komuro, Issei; Kobayashi, Yoshio

doi:10.1016/j.yjmcc.2015.12.026

Cited by 42 publications

(24 citation statements)

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“…29) Our group recently reported that DPP-4 inhibition has direct protec- tive effects on post-MI heart by inducing an antiapoptotic effect and inhibiting a decrease in vessel number via the SDF-1α/CXCR4-mediated STAT3 signaling pathway. 31) Furthermore, we confirmed that myocardial DPP-4 activity was significantly increased in HF mice compared with non-HF mice.…”

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Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure

et al. 2018

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Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as antidiabetic drugs. We recently reported that DPP-4 inhibition has beneficial effects on heart failure (HF) mice model. Furthermore, we confirmed that myocardial DPP-4 activity was significantly increased in HF mice compared with non-HF mice. The aim of this study was to investigate the level of myocardial CD26 (DPP-4) expression and its association to clinical parameters in HF patients.Endomyocardial biopsy (EMB) specimens (n = 33) were obtained from HF patients who were admitted to Chiba University Hospital from June 2006 to July 2012. EMB specimens were fixed in formaldehyde and stained with Masson's trichrome staining or with anti-CD26 antibody. Patients were divided into the high CD26 density (CD26-H) or low CD26 density groups (CD26-L). DPP-4 density was compared with blood brain natriuretic peptide (BNP) level and echocardiographic parameters at one year after EMB. Although there were no significant differences in echocardiographic parameters between the CD26-H group and CD26-L group, blood BNP levels were higher in the CD26-H group than in the CD26-L group at one year after EMB. Multivariate regression analysis showed that CD26 density was also an independent determinant of blood BNP levels at one year after EMB.The level of myocardial CD26 expression might be a predictive marker of prognosis in patients with HF. (Int Heart J 2018; 59: 1303-1311

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Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure

et al. 2018

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“…However, our essential purpose of this study was to examine whether the DPP4 inhibition restores HMGB1-induced angiogenesis and tissue repair in diabetic mice after MI. A recent article by Kubota and Takano, et al 45) has demonstrated that the treatment with DPP4 inhibitor increased the ratio of endothelial cell numbers to a cardiomyocyte, improved cardiac function and decreased the infarct size in C57BL/6 mice after MI, suggesting a key role of DPP4 activity after MI in non-diabetic condition. Thus, we should consider effects of DPP4 activity on HMGB1 function in nondiabetic condition in the future study.…”

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confidence: 99%

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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“…Los inhibidores de DDP-4 (gliptinas) reducen los triglicéridos y la presión arterial, factores de riesgo cardiovascular. Además, se constató en un modelo murino de isquemia miocárdica que disminuye el tamaño de infarto y mejora la funcionalidad miocárdica 40 . Sin embargo, en los ensayos clínicos SAVOR-TIMI, EXAMINE Y TECOS, las gliptinas no mostraron ser superiores al tratamiento con otros fármacos [41][42][43] .…”

Section: Manejo Clínico Y Terapias Convencionalesunclassified

Diabetes mellitus tipo 2 y cardiopatía isquémica: fisiopatología, regulación génica y futuras opciones terapéuticas

et al. 2018

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Diabetes mellitus tipo 2 y cardiopatía isquémica: fisiopatología, regulación génica y futuras opciones terapéuticas En los últimos años, la diabetes mellitus tipo 2 (DM2) ha evolucionado en forma epidémica, experimentando un rápido crecimiento y afectando a millones de individuos a nivel mundial. La cardiopatía isquémica es la principal causa de mortalidad en los pacientes diabé-ticos, quienes poseen un mayor riesgo cardiovascular respecto a los no diabéticos. La DM2 y la cardiopatía isquémica se caracterizan por ser prevenibles, sin embargo, existen diversos factores de riesgo comunes que contribuyen a su desarrollo. Los mecanismos que explican la ateroesclerosis acelerada y el incremento de riesgo de enfermedades cardiovasculares en los pacientes diabéticos tipo 2 incluyen a la hiperglicemia, dislipidemia y la inflamación del endotelio vascular. La diabetes es resultado de una interacción compleja entre la genética y el medio ambiente. Recientemente se han descrito varios genes implicados en el desarrollo de la diabetes y cardiopatía isquémica y que podrían significar nuevas opciones terapéuticas. En este artículo se revisa la relación entre ambas patologías, los mecanismos moleculares y el descubrimiento de factores de riesgo genéticos comunes y su implicancia en el desarrollo de nuevos blancos terapéuticos.

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DPP-4 inhibition has beneficial effects on the heart after myocardial infarction

Cited by 42 publications

References 35 publications

Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure

Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure

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

Diabetes mellitus tipo 2 y cardiopatía isquémica: fisiopatología, regulación génica y futuras opciones terapéuticas

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