High mobility group box 1 is a novel substrate of dipeptidyl peptidase-IV

Marchetti, Carlo; Carlo, Anna Di; Facchiano, Francesco; Senatore, Cinzia; Cristofaro, Raimondo De; Luzi, Alessio; Federici, Massimo; Romani, Marta; Napolitano, Monica; Capogrossi, Maurizio C.; Germani, Antonia

doi:10.1007/s00125-011-2213-6

Cited by 50 publications

(46 citation statements)

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“…36) Furthermore, Marchetti, et al proved that HMGB-1 was degraded by DPP4 in in vitro experiments and the inhibition of DPP4 enhanced tissue angiogenesis in a murine skin-wound model. 20) In the present study, we firstly demonstrated in vivo that cardio-protective effects, such as promotion of angiogenesis, suppression of cardiac remodeling, and enhancement of VEGF expression in the peri-infarct area, were reversed in diabetic state and ameliorated by administration of DPP4 inhibitor in the TG mice. However, these reactions could not be observed in the WT mice.…”

Section: Discussionmentioning

confidence: 58%

“…With regards to angiogenesis, HMGB1 promotes tissue angiogenesis by increasing the production of proangiogenic cytokines including VEGF, TNF-α, and IL-8 from endothelial cells and macrophages. 34,35) DPP4, a type of peptidase and one of the therapeutic targets for DM, reportedly degrades and inactivates not only incretin hormones but also other substances, including SDF-1, BNP, and substance P. 19) Because HMGB1 has a component of partial DPP4 cleavage sites, 20) it can also be degraded and inactivated by DPP4 in vivo. Straino, et al reported that HMGB1 levels of mice skin tissue were decreased in the diabetic state, and HMGB1 application to skin wounds promoted the tissue angiogenesis and wound healing.…”

Section: Discussionmentioning

confidence: 99%

“…sacrifice sacrifice peptides with a role in the regulation of the cardiovascular system, such as stromal-cell-derived factor-1 (SDF-1), Btype natriuretic peptide (BNP) and substance P, as well as other peptides. 19) Although some reports have claimed that HMGB1 can also be degraded by DPP4, 20) it still remains unclear as to whether DPP4 cleaves HMGB1 in vivo.…”

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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: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Similarly, TLR4 and NF-kB expression was increased in obstructed kidneys and decreased in mice treated with LC15-0444. Considering that HMGB1 can be released into the extracellular space from damaged proximal tubule cells or infiltrating activated macrophages, 11,12 it is possible that LC15-0444 treatment reduces macrophage infiltration in proximal tubule cells and suppresses HMGB1 expression in the kidney. The role of HMGB1 in tubulointerstitial fibrosis merits further study.…”

Section: Discussionmentioning

confidence: 99%

“…8 Recently, investigations of DPPIV have focused on identifying new physiologically relevant substrates, such as RANTES, neuropeptide Y, and substance P. 9,10 High-mobility group box-1 (HMGB-1) protein is a cytokine identified in 2012 as a substrate of DPPIV that mediates responses to infection, injury, and inflammation. 11,12 A 2012 paper proposed HMGB-1 as a causative factor in renal damage. 13 DPPIV has high expression levels and activity in the kidney, and is found on the apical/brush border surface of proximal renal tubular cells and in the urine.…”

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Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

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