Dipeptidyl Peptidase III Research Articles

The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock

BackgroundData to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin–angiotensin–aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock.MethodsThe DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events.DiscussionWith an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial.Trial registrationClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

Circulating Dipeptidyl Peptidase 3 Modulates Systemic and Renal Hemodynamics Through Cleavage of Angiotensin Peptides.

High circulating DPP3 (dipeptidyl peptidase 3) has been associated with poor prognosis in critically ill patients with circulatory failure. In such situation, DPP3 could play a pathological role, putatively via an excessive angiotensin peptides cleavage. Our objective was to investigate the hemodynamics changes induced by DPP3 in mice and the relation between the observed effects and renin-angiotensin system modulation. Ten-week-old male C57Bl/6J mice were subjected to intravenous injection of purified human DPP3 or an anti-DPP3 antibody (procizumab). Invasive blood pressure and renal blood flow were monitored throughout the experiments. Circulating angiotensin peptides and catecholamines were measured and receptor blocking experiment performed to investigate the underlying mechanisms. DPP3 administration significantly increased renal blood flow, while blood pressure was minimally affected. Conversely, procizumab led to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamines release that explains blood pressure maintenance upon DPP3 administration. High circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release.

Dipeptidyl-peptidase 3 and IL-6: potential biomarkers for diagnostics in COVID-19 and association with pulmonary infiltrates

Coronavirus SARS-CoV-2 spread worldwide, causing a respiratory disease known as COVID-19. The aim of the present study was to examine whether Dipeptidyl-peptidase 3 (DPP3) and the inflammatory biomarkers IL-6, CRP, and leucocytes are associated with COVID-19 and able to predict the severity of pulmonary infiltrates in COVID-19 patients versus non-COVID-19 patients. 114 COVID-19 patients and 35 patients with respiratory infections other than SARS-CoV-2 were included in our prospective observational study. Blood samples were collected at presentation to the emergency department. 102 COVID-19 patients and 28 non-COVID-19 patients received CT imaging (19 outpatients did not receive CT imaging). If CT imaging was available, artificial intelligence software (CT Pneumonia Analysis) was used to quantify pulmonary infiltrates. According to the median of infiltrate (14.45%), patients who obtained quantitative CT analysis were divided into two groups (> median: 55 COVID-19 and nine non-COVID-19, ≤ median: 47 COVID-19 and 19 non-COVID-19). DPP3 was significantly elevated in COVID-19 patients (median 20.85 ng/ml, 95% CI 18.34–24.40 ng/ml), as opposed to those without SARS-CoV-2 (median 13.80 ng/ml, 95% CI 11.30–17.65 ng/ml; p < 0.001, AUC = 0.72), opposite to IL-6, CRP (each p = n.s.) and leucocytes (p < 0.05, but lower levels in COVID-19 patients). Regarding binary logistic regression analysis, higher DPP3 concentrations (OR = 1.12, p < 0.001) and lower leucocytes counts (OR = 0.76, p < 0.001) were identified as significant and independent predictors of SARS-CoV-2 infection, as opposed to IL-6 and CRP (each p = n.s.). IL-6 was significantly increased in patients with infiltrate above the median compared to infiltrate below the median both in COVID-19 (p < 0.001, AUC = 0.78) and in non-COVID-19 (p < 0.05, AUC = 0.81). CRP, DPP3, and leucocytes were increased in COVID-19 patients with infiltrate above median (each p < 0.05, AUC: CRP 0.82, DPP3 0.70, leucocytes 0.67) compared to infiltrate below median, opposite to non-COVID-19 (each p = n.s.). Regarding multiple linear regression analysis in COVID-19, CRP, IL-6, and leucocytes (each p < 0.05) were associated with the degree of pulmonary infiltrates, as opposed to DPP3 (p = n.s.). DPP3 showed the potential to be a COVID-19-specific biomarker. IL-6 might serve as a prognostic marker to assess the extent of pulmonary infiltrates in respiratory patients.

Identification of SH2 Domain-Containing Protein 3C as a Novel, Putative Interactor of Dipeptidyl Peptidase 3.

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent exopeptidase with broad specificity for four to eight amino acid residue substrates. It has a role in the regulation of oxidative stress response NRF2-KEAP1 pathway through the interaction with KEAP1. We have conducted stable isotope labeling by amino acids in a cell culture coupled to mass spectrometry (SILAC-MS) interactome analysis of TRex HEK293T cells using DPP3 as bait and identified SH2 Domain-Containing Protein 3C (SH2D3C) as prey. SH2D3C is one of three members of a family of proteins that contain both the SH2 domain and a domain similar to guanine nucleotide exchange factor domains of Ras family GTPases (Ras GEF-like domain), named novel SH2-containing proteins (NSP). NSPs, including SH2D3C (NSP3), are adaptor proteins involved in the regulation of adhesion, migration, tissue organization, and immune response. We have shown that SH2D3C binds to DPP3 through its C-terminal Ras GEF-like domain, detected the colocalization of the proteins in living cells, and confirmed direct interaction in the cytosol and membrane ruffles. Computational analysis also confirmed the binding of the C-terminal domain of SH2D3C to DPP3, but the exact model could not be discerned. This is the first indication that DPP3 and SH2D3C are interacting partners, and further studies to elucidate the physiological significance of this interaction are on the way.

Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes.

Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS). Plasma cDPP3 levels were assessed at baseline and 12-24 hours after presentation in patients with ACS prospectively enrolled into the multicentre SPUM-ACS study (n = 4787). Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score (per log-2 increase, hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.05-1.82, P = 0.021). High cDPP3 was as an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < 0.001) and at 1 year (HR 1.61, 95% CI 1.28-2.02, P < 0.001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 hours were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < 0.001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < 0.001). Results were consistent across various patient subgroups. This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment.

Associations of dipeptidyl-peptidase 3 with short-term outcome in a mixed admission ICU-cohort

PurposeBiomarkers independently associated with outcome of intensive care unit (ICU) patients can improve risk assessment. The cytosolic protease dipeptidyl-peptidase 3 (DPP3) is released into the circulation upon cell necrosis. We aimed to investigate the prognostic properties of cDPP3 in a mixed-admission ICU cohort. Materials and methodsProspective observational study in 650 adult ICU patients. cDPP3 concentrations were measured at ICU admission (day 1), and on days 2 and 3. ResultscDPP3 concentrations on days 1 and 2, but not on day 3 were associated with 28-day mortality; HR 1.36 (95%CI 1.01–1.83, p = 0.043) and HR 1.49 (95%CI 1.16–1.93, p = 0.002) for days 1 and 2, respectively. cDPP3 was also associated with acute kidney injury (AKI), with OR's of 1.31 (95%CI 1.05–1.64, p = 0.016), 1.87 (95%CI 1.51–2.34, p < 0.001) and 1.49 (95%CI 1.16–1.92, p = 0.002) for measurements performed on days 1, 2, and 3, respectively. In multivariate analyses including SOFA or APACHE-II scores, cDPP3 assessed at day 2 of admission remained an independent predictor of mortality and all-stage AKI. ConclusionsIn a mixed-ICU cohort, cDPP3 concentrations after start of initial treatment were independently associated with both mortality and development of AKI. Therefore, measurement of cDPP3 can improve risk-stratification provided by established disease severity scores.

The source of liberation of dipeptidyl peptidase 3 (DPP3), a newly emerged cardiac biomarker, in pathological situations

Dipeptidyl peptidase 3 (DPP3) is a zinc dependent aminopeptidase that cleaves dipeptides from the N- terminus of several substrates such as angiotensins. DPP3 is an intracellular protein. It has also been detected in the circulation of healthy and sick individuals being known as circulating DPP3 (cDPP3). cDPP3 has emerged as a biomarker and a therapeutic target in acute cardiac stress. Despite the well-known ubiquitous expression of DPP3 in physiological situations, its expression and source of release in pathological conditions remain to be explored. This study aimed to evaluate DPP3 expression in cardiac stress conditions. C57BL6/J mice were subjected to cardiac dysfunction using two different pharmacological models: 1- Isoproterenol (ISO) model: injection of 150 mg/kg of ISO every 12 h for two days; 2- Doxorubicin (DOX) model: injection of 4 mg/kg/day of DOX for 6 days. Blood samples, organs, and bone marrow (cells and supernatant) were collected at the end of each protocol. DPP3 protein expression was evaluated by western-blot. Enzymatic activity of DPP3 was measured by luminometric immunoassay (DPP3-LIA). Our results showed different patterns of DPP3 expression based on pathological condition. Mice in ISO group showed a significantly higher DPP3 protein expression in bone marrow, both cells and supernatant, compared to control group (1.8X, P < 0.05). In consistence with this, DPP3 enzymatic activity was significantly increased in both bone marrow supernatant and plasma in these mice (1.4X, P < 0.05) and (1.3X, P < 0.05) respectively, indicating that bone marrow might be responsible for releasing DPP3 into the surrounding microenvironment and into the circulation. However, DPP3 expression was decreased in the spleen of ISO mice (0.5X, P < 0.05). This decrease could be explained by spleen-contraction following ISO injection, a phenomenon already described in the literature, allowing greater release of red blood cells, highly expressing DPP3, into bloodstream. On the other hand, in Dox model, only an up-regulation of DPP3 in the spleen (1.7X, P < 0.05) was reported. An increase of DPP3 activity in plasma but not in bone marrow supernatant was remarked. Our results show that DPP3 expression varies based on the type of model used to induce cardiac dysfunction. It seems that main hematopoietic organs (spleen and bone marrow) might represent sources of cDPP3.

Circulating DPP3 is an early predictor of mortality and organ support in patients with cardiogenic shock: Post-hoc analyses of the ACCOST-HH trial

Dipeptidyl Peptidase 3 (DPP3) is a protease which has recently been shown to have an increased importance in the cardiovascular system. Previous studies demonstrated that elevated circulating DPP3 concentration (cDPP3) is an early predictor of short-term outcome in cardiogenic shock, mostly of ischemic origin. Whether cDPP3 is related to outcome in a more diverse cohort of cardiogenic shock remains unknown. To evaluate the association between cDPP3 levels and 30-days mortality in a mixed cardiogenic shock population. Post-hoc analysis of the ACCOST-HH cohort, a prospective, double-blind, multicentre, randomized, placebo-controlled trial on safety and efficacy of Adrecizumab, an adrenomedullin-modulating antibody, in cardiogenic shock patients, was performed. Values of cDPP3 under 40 ng/mL were considered low concentrations, and above defined as high. In all, 48% of the patient's cohort with high cDPP3 at admission died within 30 days after inclusion, whereas mortality was only 31% in the low cDPP3 group (HR = 1.8 (95% CI = 1.1–3.1), P < 0.05). Mortality in patients with non-ischemic cause of CS was much higher in the high cDPP3 group (HR 2.6, 95% CI = 1.2–5.6). The median number of days without need of cardiovascular support in the low cDPP3 group was 20.5 whereas the median in the high cDPP3 group was 3 days (P = 0.0005). There was a significant increase in need for renal replacement therapy when cDPP3 was high compared to when it was low at admission (56% vs. 22%, P < 0.05). In addition, elevated cDPP3 was associated with a higher need for invasive mechanical ventilation (90% in the high cDPP3 group vs. 74% in the low cDPP3 group, P < 0.05). Furthermore, kinetics of cDPP3 from 0 to 72 hours after admission for CS had a significant impact on outcome: when cDPP3 levels were low at both timepoints (LL-group) or when cDPP3 was initially high but low at 72 h (HL group), 30 day-mortality was significantly decreased when compared to the group with constantly high cDPP3 levels (HH). Sex- and age-adjusted HR for LL vs. HH was 0.2 (95% CI 0.1–0.4), and HR for HL vs. HH was 0.2 (95% CI 0.1–0.3). In cardiogenic shock, cDPP3 is an early predictor of mortality where low concentrations are correlated with improved survival. Moreover, monitoring cDPP3 kinetics is relevant for further assessment of patient care and therapy.

Dipeptidyl Amino-Peptidase 3 (DPP3) as an Early Marker of Severity in a Patient Population with Cardiogenic Shock.

Dipeptidyl amino-peptidase 3 (DPP3) is an aminopeptidase that is released into circulation upon cell death. DPP3 is involved in the degradation of angiotensins, enkephalines, and endomorphines. It has been shown that circulating DPP3 (cDPP3) plasma concentration increases in cardiogenic shock (CS) patients and correlates with high mortality risk. Cardiogenic shock is a life-threatening syndrome associated with organ hypoperfusion. One of the common causes of CS is acute myocardial infarction (AMI). This study aimed to investigate if cDPP3 levels are associated with CS severity and the need for ventilation in patients suffering from CS. Fifteen patients with CS were included in this study. Six patients were invasively ventilated. The values of cDPP3 were higher in ventilated patients than in non-ventilated patients at admission, 3 h, and 24 h after admission in the intensive care unit. Patients with pulmonary hypertension at admission also showed high cDPP3 values at all time points. Furthermore, high cDPP3 levels were associated with reduced stroke volume. Our results suggest that cDPP3 could predict CS progression and guide therapy escalation.

Biomarkers as Prognostic Predictors and Therapeutic Guide in Critically Ill Patients: Clinical Evidence.

A biomarker is a molecule that can be measured in a biological sample in an objective, systematic, and precise way, whose levels indicate whether a process is normal or pathological. Knowing the most important biomarkers and their characteristics is the key to precision medicine in intensive and perioperative care. Biomarkers can be used to diagnose, in assessment of disease severity, to stratify risk, to predict and guide clinical decisions, and to guide treatments and response to them. In this review, we will analyze what characteristics a biomarker should have and how to ensure its usefulness, and we will review the biomarkers that in our opinion can make their knowledge more useful to the reader in their clinical practice, with a future perspective. These biomarkers, in our opinion, are lactate, C-Reactive Protein, Troponins T and I, Brain Natriuretic Peptides, Procalcitonin, MR-ProAdrenomedullin and BioAdrenomedullin, Neutrophil/lymphocyte ratio and lymphopenia, Proenkephalin, NefroCheck, Neutrophil gelatinase-associated lipocalin (NGAL), Interleukin 6, Urokinase-type soluble plasminogen activator receptor (suPAR), Presepsin, Pancreatic Stone Protein (PSP), and Dipeptidyl peptidase 3 (DPP3). Finally, we propose an approach to the perioperative evaluation of high-risk patients and critically ill patients in the Intensive Care Unit (ICU) based on biomarkers.

DPP3: From biomarker to therapeutic target of cardiovascular diseases.

Cardiovascular disease is the leading cause of death globally among non-communicable diseases, which imposes a serious socioeconomic burden on patients and the healthcare system. Therefore, finding new strategies for preventing and treating cardiovascular diseases is of great significance in reducing the number of deaths and disabilities worldwide. Dipeptidyl peptidase 3 (DPP3) is the first zinc-dependent peptidase found among DPPs, mainly distributes within the cytoplasm. With the unique HEXXGH catalytic sequence, it is associated with the degradation of oligopeptides with 4 to 10 amino acids residues. Accumulating evidences have demonstrated that DPP3 plays a significant role in almost all cellular activities and pathophysiological mechanisms. Regarding the role of DPP3 in cardiovascular diseases, it is currently mainly used as a biomarker for poor prognosis in patients with cardiovascular diseases, suggesting that the level of DPP3 concentration in plasma is closely linked to the mortality of diseases such as cardiogenic shock and heart failure. Interestingly, it has been reported recently that DPP3 regulates blood pressure by interacting with the renin-angiotensin system. In addition, DPP3 also participates in the processes of pain signaling, inflammation, and oxidative stress. But the exact mechanism by which DPP3 affects cardiovascular function is not clear. Hence, this review summarizes the recent advances in the structure and catalytic activity of DPP3 and its extensive biological functions, especially its role as a therapeutic target in cardiovascular diseases. It will provide a theoretical basis for exploring the potential value of DPP3 as a therapeutic target for cardiovascular diseases.

Evaluation of autoantibody signatures in pituitary adenoma patients using human proteome arrays.

To identify the specific diagnostic biomarkers related to pituitary adenomas (PAs), we performed serological antibody profiles for three types of PAs, namely Acromegaly, Cushing's and Nonfunctional Pituitary Adenomas (NFPAs), using the human proteome (HuProt) microarray. This is the first study describing the serum autoantibody profile of PAs. We performed serological autoantibody profiling of four healthy controls, four Acromegaly, three Cushing's and three NFPAs patient samples to obtain their autoantibody profiles, which were used for studying expression, interaction and altered biological pathways. Further, significant autoantibodies of PAs were compared with data available for glioma, meningioma and AAgAtlas for their specificity. Autoantibody profile of PAs led to the identification of differentially expressed significant proteins such as AKNAD1 (AT-Hook Transcription Factor [AKNA] Domain Containing 1), NINJ1 (Nerve injury-induced protein 1), L3HYPDH (Trans-3-hydroxy-L-proline dehydratase), RHOG (Rho-related GTP-binding protein) and PTP4A1 (Protein Tyrosine Phosphatase Type IVA 1) in Acromegaly. Protein ABR (Active breakpoint cluster region-related protein), ST6GALNAC6 (ST6 N-acetylgalactosaminide alpha-2, 6-sialyltransferase 6), NOL3 (Nucleolar protein 3), ANXA8 (Annexin A8) and POLR2H (RNA polymerase II, I and III subunit H) showed an antigenic response in Cushing's patient's serum samples. Protein dipeptidyl peptidase 3 (DPP3) and reticulon-4 (RTN4) exhibited a very high antigenic response in NFPA patients. These proteins hold promise as potential autoantibody biomarkers in PAs.

Role of dipeptidyl peptidase 3 (DPP3) in cardiomyocyte toxicity induced by cancer cells and/or chemotherapy treatment

Cardiotoxicity is an important side effect of chemotherapy such as Doxorubicin (Dox). Developing new biomarkers of cardiotoxicity is important to improve the cardiologic monitoring of cancer patients. Dipeptidyl peptidase 3 (DPP3), a zinc-dependent metallopeptidase, has emerged as a new biomarker and therapeutic target of acute cardiac dysfunction. Considering DPP3′ effects on cardiac function, and its increased expression in some types of cancer, we aimed to investigate a possible implication of DPP3 in cancer and/or chemotherapy induced cardiotoxicity. To evaluate DPP3 expression in cancer and in cardiomyocytes cell lines, the effect of DPP3 inhibition on cardiomyocytes survival and the effect of cancer cells secretome, in the presence or absence of DPP3, on cardiomyocytes survival. Our study was conducted, in vitro, in two cell lines: rat cardiomyocytes (H9C2) and murine ovarian cancer cells (ID8). Different treatments were applied; Dox (0.5 μM), DPP3 (0.62 or 6.2 μg/mL) alone or in combination with Dox, in addition to a treatment with anti-DPP3 antibody, procizumab PCZ (4 ng/mL). To investigate the direct effect of cancer on cardiomyocytes, the effect of ID8 secretome (non-treated, treated with Dox 0.5 μM, or with Dox 0.5 μM + PCZ 40 ng/mL), on cardiomyocytes was studied. Cell survival was evaluated after 24 h treatment. Finally, DPP3 protein expression was assessed by Western blot. Our results showed a significant decrease of H9C2 survival when treated with Dox 0.5 μM (×0.32, P < 0.05), reflecting its cardiotoxicity. DPP3 protein expression increased in both ID8 (×19, P < 0.05) and H9C2 (×3.5, P < 0.05) when treated with Dox. Treating ID8 with DPP3 0.62 μg/mL increased their survival when no treatment was applied (×1.52, P < 0.05), however, this increase was not significant with the higher concentration of DPP3. In the presence of Dox treatment, an increase of H9C2 survival was induced by DPP3, in both concentrations; 0.62 μg/mL (×1.68, P < 0.05), 62 μg/mL (×1.83, P < 0.05), in comparison to Dox alone. When blocking DPP3 by PCZ, the survival of H9C2, treated with Dox or with ID8 secretome treated with Dox, has increased (×1.71, P < 0.05) and (×1. 86, P < 0.05), respectively. The effect of PCZ on cardiotoxicity along aside with the increased expression of DPP3 induced by Dox may reflect a possible implication of DPP3 in Dox-induced cardiotoxicity.

Circulating dipeptidyl peptidase 3 modulates hemodynamics and the renin-angiotensin-aldosterone system in mice

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent metallopeptidase cleaving the N-terminal extremity of various bioactive peptides including angiotensins. Angiotensin II is a vasoactive peptide also known to have an inotropic effect. Although the plasmatic concentration of DPP3 is low in healthy human and animals, an increase in plasmatic DPP3 concentration and activity has been observed during circulatory failure. In such situation DPP3 could play a pathological role, putatively via an excess in angiotensin cleavage. To investigate 1. Hemodynamics changes induced by DPP3 in healthy mice; 2. Concomitant changes in circulating renin-angiotensin-aldosterone system (RAAS) mediators. Healthy, 10-week-old C57BL/6J male mice were subjected to intravenous injection of purified human DPP3 (0.55 mg/kg), anti-DPP3 antibody (Procizumab, 10 mg/kg) or phosphate-buffered saline (PBS). Cardiovascular function was monitored using echocardiography, invasive blood pressure by catheterism of the femoral artery and renal blood flow with an invasive time-of-flight flowmeter. Circulating angiotensin peptides, aldosterone, and renin activity were measured by liquid chromatography-mass spectrometry/mass spectroscopy. DPP3 injection induced a decrease in left ventricular systolic function as measured by the left ventricular shortening fraction with a maximal depression of −12 ± 8% ( P = 0.01) and an increase in mean renal blood flow (maximal increase +45 ± 18%, P = 0.02) gradually returning to baseline values in 120 min and 30 min, respectively. Invasive blood pressure remained stable throughout the experiment. Additionaly; DPP3 were associated with a significant decrease in circulating angiotensin II (−66%, P < 0.01), angiotensin III (−82%, P < 0.001) and angiotensin IV (−68%, P < 0.001) and a significant increase in angiotensin I (+108%, P = 0.02) compared to PBS injected mice. Conversely, procizumab injection resulted in increased circulating angiotensin II (+113%, P < 0.01), angiotensin III (+75%, P = 0.02), angiotensin 1-5 (+167%, P = 0.02) angiotensin 1-7 (+60%, P = 0.01) as well as increased aldosterone (+49%, P = 0.04), when compared to PBS injected mice. DPP3 injection induced cardiac dysfunction and renal blood flow increase in healthy mice. Additionally, DPP3 injection is associated with a decrease in angiotensins levels including angiotensin II, which was reversed with procizumab. Future work on the relation between hemodynamic changes and DPP3-induced modulation of the RAAS is needed.

The emerging role of dipeptidyl peptidase 3 in pathophysiology.

Dipeptidyl peptidase 3 (DPP3), a zinc-dependent aminopeptidase, is a highly conserved enzyme among higher animals. The enzyme cleaves dipeptides from the N-terminus of tetra- to decapeptides, thereby taking part in activation as well as degradation of signalling peptides critical in physiological and pathological processes such as blood pressure regulation, nociception, inflammation and cancer. Besides its catalytic activity, DPP3 moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1-Nrf2 mediated antioxidative response. The enzyme is also recognized as a key modulator of the renin-angiotensin system. Recently, DPP3 has been attracting growing attention within the scientific community, which has significantly augmented our knowledge of its physiological relevance. Herein, we review recent advances in our understanding of the structure and catalytic activity of DPP3, with a focus on attributing its molecular architecture and catalytic mechanism to its wide-ranging biological functions. We further highlight recent intriguing reports that implicate a broader role for DPP3 as a valuable biomarker in cardiovascular and renal pathologies and furthermore discuss its potential as a promising drug target.

Estimation of bioactive peptide content of milk from different species using an in silico method.

This study assessed the bioactive peptides content of milk from different species, including humans, camel, bovine, buffalo, donkey, sheep, goat, and horse. The highest and lowest concentrations of total digestion-resistant peptides were estimated in sheep and human milk. Donkey milk casein contains a higher angiotensin-converting enzyme (ACE) inhibitory, dipeptidyl peptidase III (DPP-III) inhibitory, DPP-IV inhibitory, and antioxidant peptides. On the other hand, camel whey protein contains the highest ACE-inhibitory peptides. To discover BPs with immunomodulatory and cholesterol-lowering functions, goat milk casein and sheep milk whey protein can be considered, respectively.

The value of bioactive adrenomedullin and dipeptidyl peptidase 3 to predict short-term unfavourable outcomes after cardiac surgery: A prospective cohort study.

Adrenomedullin (ADM) is a key regulator of endothelial barrier function and vascular tone. Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Increased levels of bioactive ADM (bio-ADM) and circulating DPP3 (cDPP3) were found to predict short-term outcome in cardiogenic shock patients. To investigate the unknown temporal profiles of bio-ADM and cDPP3 and their association with short-term outcome following cardiac surgery. Prospective observational study of 203 adult cardiac surgery patients admitted to the intensive care unit (ICU) postoperatively. Plasma bio-ADM and cDPP3 levels were measured at ICU admission (day 1) and on days 2 and 3. Biomarker prediction of prolonged vasopressor dependency (>3 days), acute kidney injury (AKI) and prolonged ICU length of stay (ICU-LOS) (>3 days). bio-ADM and cDPP3 levels displayed distinct temporal profiles following cardiac surgery. cDPP3 levels were highest on day 1 and strongly correlated with surgical complexity and duration but subsequently normalised on day 2 in most patients. In contrast, bio-ADM levels on day 1 were within the normal range but subsequently increased. Day 2 bio-ADM levels were strongly associated with study outcomes: the area under the receiver-operating curves (AUROC) were 0.82 (95% CI, 0.72 to 0.92) for prolonged vasopressor dependency, 0.87 (0.81 to 0.92) for AKI and 0.82 (0.75 to 0.90) for prolonged ICU-LOS (all P < 0.0001). cDPP3 levels on day 2 also predicted these outcomes, albeit to a lesser extent, with AUROCs of 0.73 (95% CI, 0.64 to 0.81) for prolonged vasopressor dependency, 0.69 (0.61 to 0.77) for AKI and 0.70 (0.62 to 0.79) for prolonged ICU-LOS (all P < 0.0001). Following cardiac surgery, increased bio-ADM levels are strongly associated with unfavourable short-term outcomes, whereas cDPP3 levels are mainly related to surgery complexity and duration. On the basis of these findings, ADM-modulating therapies may have beneficial effects in cardiac surgery patients whereas DPP3-targeted therapies should be reserved for patient categories with higher baseline disease severity.

Dipeptidyl peptidase-3 is associated with severity of liver disease and circulatory complications in patients with cirrhosis

Background Patients with cirrhosis suffer from a complex multiorgan disturbance and their prognosis is influenced by the development of portal hypertension and systemic circulatory dysfunction. Although non-invasive techniques such as transient elastography aid in early detection, there is an unmet need for reliable markers of these clinically significant complications. Methods We conducted an exploratory single-center study investigating dipeptidyl peptidase-3 (DPP3) concentrations in various vascular beds in a cohort of 48 patients with cirrhosis and 16 healthy controls. Liver vein catheterisation with sampling from femoral artery and femoral, renal and hepatic veins as well as measurement of hepatic pressure and liver function via indocyanine green and galactose elimination tests were performed. Results DPP3 concentrations were higher in cirrhotic patients compared to controls (12.6 vs. 7.4 ng/mL, p = 0.006) and increased according to the severity of cirrhosis. DPP3 associated with MELD-Na score, Child class, indocyanine green clearance, increased DPP3 with the increased hepatic venous pressure gradient (p = 0.015) as well as increased heart rate and reduced systemic vascular resistance. DPP3 concentrations predicted the presence of clinically significant portal hypertension in cirrhotic patients (AUROC 0.78, 95% CI 0.65–0.9). Conclusion DPP3 is a promising marker for portal hypertension and systemic hemodynamic changes in cirrhosis.

A Novel Indicator of Myocardial Injury after Acute Myocardial Infarction: 'DPP-3'.

Dipeptidyl peptidase 3 (DPP-3) is an intracellular enzyme that causes hemodynamic instability and cardiac depression in several cases such as cardiogenic shock, sepsis and burns where DPP-3 is released into the blood due to cell death. Data on the effect of higher DPP-3 levels on acute coronary syndrome (ACS) patients are currently lacking. The aim of this study was to evaluate the effect of DPP-3 levels on ACS patients. In this prospective study, we included ACS patients including STEMI and non-STEMI groups and a control group to compare various demographic, echocardiographic and laboratory parameters including DPP-3. DPP-3 levels were measured at 24th, 48th, and 72nd h from the onset of symptoms in ACS patients and then compared with left ventricle ejection fraction (LVEF) for the assessment of left ventricle systolic function. A total of 70 ACS patients (age 62.5 ± 11 years, 68.6% male) were recruited and 48 normal individuals were included as control group (age 61.1 ± 10 years, 66.7% male). It has been demonstrated that DPP-3 levels are significantly higher in the ACS group than the control group like troponin I levels. DPP-3 levels were found to be one of the independent predictors of LVEF similar to NT-proBNP and troponin I. This study suggests that DPP-3 could be an important indicator of myocardial depression predicting left ventricle systolic function in ACS.

DPP3/CDK1 contributes to the progression of colorectal cancer through regulating cell proliferation, cell apoptosis, and cell migration

At present, colorectal cancer (CRC) has become a serious threat to human health in the world. Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase that may be involved in several physiological processes. However, whether DPP3 affects the development and progression of CRC remains a mystery. This study is the first to demonstrate the role of DPP3 in CRC. Firstly, the results of immunohistochemistry analysis showed the upregulation of DPP3 in CRC tissues compared with normal tissues, which is statistically analyzed to be positively correlated with lymphatic metastasis, pathological stage, positive number of lymph nodes. Moreover, the high expression of DPP3 predicts poor prognosis in CRC patients. In addition, the results of cell dysfunction experiments clarified that the downregulation of DPP3 significantly inhibited cell proliferation, colony formation, cell migration, and promoted apoptosis in vitro. DPP3 depletion could induce cell apoptosis by upregulating the expression of BID, BIM, Caspase3, Caspase8, HSP60, p21, p27, p53, and SMAC. In addition, downregulation of DPP3 can reduce tumorigenicity of CRC cells in vivo. Furthermore, CDK1 is determined to be a downstream target of DPP3-mediated regulation of CRC by RNA-seq, qPCR, and WB. The interaction between DPP3 and CDK1 shows mutual regulation. Specifically, downregulation of DPP3 can accentuate the effects of CDK1 knockdown on the function of CRC cells. Overexpression of CDK1 alleviates the inhibitory effects of DPP3 knockdown in CRC cells. In summary, DPP3 has oncogene-like functions in the development and progression of CRC by targeting CDK1, which may be an effective molecular target for the prognosis and treatment of CRC.