DPP3

Outside cells, DPP3, referred to as circulating DPP3 (cDPP3), is detected in various extracellular fluids, including cerebrospinal fluid, seminal plasma, and retroplacental plasma in low levels.{{cite journal | vauthors = Shimamori Y, Watanabe Y, Fujimoto Y | title = Purification and characterization of dipeptidyl aminopeptidase III from human placenta | journal = Chemical & Pharmaceutical Bulletin | volume = 34 | issue = 8 | pages = 3333–3340 | date = August 1986 | pmid = 3791505 | doi = 10.1248/cpb.34.3333 }}{{cite journal | vauthors = Vanha-Perttula, T | title = Dipeptidyl peptidase III and alanyl aminopeptidase in the human seminal plasma: Origin and biochemical properties | journal = Clin. Chim. Acta | volume = 177 | pages = 179–195 |date= October 1988| issue = 2 | doi = 10.1016/0009-8981(88)90140-4 | pmid = 2906822 }}{{cite journal | vauthors = Sato H, Kimura K, Yamamoto Y, Hazato T | title = [Activity of DPP III in human cerebrospinal fluid derived from patients with pain] | language = Japanese | journal = Masui. The Japanese Journal of Anesthesiology | volume = 52 | issue = 3 | pages = 257–263 | date = March 2003 | pmid = 12703067 | doi = }} In healthy adults, cDPP3 is present in plasma at a median concentration of 10 ng/mL, with an upper normal range of 22 ng/mL (97.5th percentile). However, in populations resembling ICU patients (e.g., older individuals with comorbidities), median cDPP3 levels of 14 ng/mL, with an upper range of 30 ng/mL, as defined by the 95th percentile.{{cite journal | vauthors = Rehfeld L, Funk E, Jha S, Macheroux P, Melander O, Bergmann A | title = Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples | journal = The Journal of Applied Laboratory Medicine | volume = 3 | issue = 6 | pages = 943–953 | date = May 2019 | pmid = 31639686 | doi = 10.1373/jalm.2018.027995 }}

DPP3 degrades a variety of bioactive peptides, including angiotensins and endogenous opioids like enkephalins and endomorphins{{cite journal | vauthors = Barsun M, Jajcanin N, Vukelić B, Spoljarić J, Abramić M | title = Human dipeptidyl peptidase III acts as a post-proline-cleaving enzyme on endomorphins | journal = Biological Chemistry | volume = 388 | issue = 3 | pages = 343–348 | date = March 2007 | pmid = 17338643 | doi = 10.1515/BC.2007.039 }}{{cite journal | vauthors = Lee CM, Snyder SH | title = Dipeptidyl-aminopeptidase III of rat brain. Selective affinity for enkephalin and angiotensin | journal = The Journal of Biological Chemistry | volume = 257 | issue = 20 | pages = 12043–12050 | date = October 1982 | pmid = 6749851 | doi = 10.1016/S0021-9258(18)33674-3| doi-access = free }} Its best-characterized substrate is angiotensin II (Ang II), a key regulator of cardiovascular and renal function. Recent research demonstrates that DPP3 actively degrades Ang II in vivo, leading to reduced blood pressure in hypertensive mice.{{cite journal | vauthors = Ferrario CM | title = Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research | journal = Journal of the Renin-Angiotensin-Aldosterone System | volume = 7 | issue = 1 | pages = 3–14 | date = March 2006 | pmid = 17083068 | doi = 10.3317/jraas.2006.003 }}{{cite journal | vauthors = Pang X, Shimizu A, Kurita S, Zankov DP, Takeuchi K, Yasuda-Yamahara M, Kume S, Ishida T, Ogita H | title = Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension | journal = Hypertension | volume = 68 | issue = 3 | pages = 630–641 | date = September 2016 | pmid = 27456521 | doi = 10.1161/HYPERTENSIONAHA.116.07357 }} In addition, DPP3 i.v. administration significantly increases renal blood flow, while blood pressure was minimally affected. Conversely, procizumab, a DPP3 inhibitor, leads 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 catecholamine release that explains blood pressure maintenance upon DPP3 administration. In conclusion, 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.

{{cite journal | vauthors = Picod A, Placier S, Genest M, Callebert J, Julian N, Zalc M, Assad N, Nordin H, Santos K, Gaudry S, Chatziantoniou C, Mebazaa A, Azibani F | title = Circulating Dipeptidyl Peptidase 3 Modulates Systemic and Renal Hemodynamics Through Cleavage of Angiotensin Peptides | journal = Hypertension | volume = 81 | issue = 4 | pages = 927–935 | date = April 2024 | pmid = 38334001 | pmc = 10956665 | doi = 10.1161/HYPERTENSIONAHA.123.21913 }}

DPP3 is a zinc-dependent enzyme that sequentially removes dipeptides from the N-terminus of bioactive substrates, typically ranging from 4 to 10 residues in length.{{cite journal | vauthors = Cruz-Diaz N, Wilson BA, Pirro NT, Brosnihan KB, Marshall AC, Chappell MC | title = Identification of dipeptidyl peptidase 3 as the Angiotensin-(1-7) degrading peptidase in human HK-2 renal epithelial cells | journal = Peptides | volume = 83 | issue = | pages = 29–37 | date = September 2016 | pmid = 27315786 | pmc = 5500233 | doi = 10.1016/j.peptides.2016.06.005 }}{{cite journal | vauthors = Prajapati SC, Chauhan SS | title = Dipeptidyl peptidase III: a multifaceted oligopeptide N-end cutter | journal = The FEBS Journal | volume = 278 | issue = 18 | pages = 3256–3276 | date = September 2011 | doi = 10.1111/j.1742-4658.2011.08275.x | pmid = 21794094 }}{{cite journal | vauthors = Malovan G, Hierzberger B, Suraci S, Schaefer M, Santos K, Jha S, Macheroux P | title = The emerging role of dipeptidyl peptidase 3 in pathophysiology | journal = The FEBS Journal | volume = 290 | issue = 9 | pages = 2246–2262 | date = May 2023 | pmid = 35278345 | doi = 10.1111/febs.16429 | doi-access = free }}

Within cells, DPP3 plays a critical role in activating the Keap1-Nrf2 antioxidant pathway, which helps combat oxidative stress. Studies have shown that DPP3 is overexpressed under conditions of oxidative stress, such as in severe heart failure models.{{cite journal | vauthors = Ren X, Yu J, Guo L, Ma H | title = Dipeptidyl-peptidase 3 protects oxygen-glucose deprivation/reoxygenation-injured hippocampal neurons by suppressing apoptosis, oxidative stress and inflammation via modulation of Keap1/Nrf2 signaling | journal = International Immunopharmacology | volume = 96 | issue = | article-number = 107595 | date = July 2021 | pmid = 33812256 | doi = 10.1016/j.intimp.2021.107595 }}{{cite journal | vauthors = Menale C, Robinson LJ, Palagano E, Rigoni R, Erreni M, Almarza AJ, Strina D, Mantero S, Lizier M, Forlino A, Besio R, Monari M, Vezzoni P, Cassani B, Blair HC, Villa A, Sobacchi C | title = Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss | journal = Journal of Bone and Mineral Research | volume = 34 | issue = 11 | pages = 2133–2148 | date = November 2019 | pmid = 31295380 | pmc = 7203631 | doi = 10.1002/jbmr.3829 }} Consequently, DPP3 knockout mice exhibit sustained oxidative stress, disrupted bone homeostasis, and dysregulation of the renin-angiotensin-aldosterone system (RAAS) peptides in the blood.{{cite journal | vauthors = Jha S, Taschler U, Domenig O, Poglitsch M, Bourgeois B, Pollheimer M, Pusch LM, Malovan G, Frank S, Madl T, Gruber K, Zimmermann R, Macheroux P | title = Dipeptidyl peptidase 3 modulates the renin-angiotensin system in mice | journal = The Journal of Biological Chemistry | volume = 295 | issue = 40 | pages = 13711–13723 | date = October 2020 | pmid = 32546481 | pmc = 7535908 | doi = 10.1074/jbc.RA120.014183 | doi-access = free }} DPP3 is highly conserved among higher animals, underscoring its biological importance.

High cDPP3 levels (>40 ng/mL) in critically ill patients are strongly associated with myocardial depression, multi-organ dysfunction, disease severity, and poor outcomes. Retrospective studies and in vivo experiments support this link, showing that intravenous DPP3 administration in healthy rodents impairs cardiac and renal function. These findings suggest that DPP3 contributes to circulatory failure by degrading vasoactive peptides like Ang II.

In summary, DPP3 is a multifunctional enzyme with significant roles in oxidative stress regulation, cardiovascular homeostasis, and disease progression. Its involvement in Ang II degradation and circulatory dysfunction highlights its potential as a therapeutic target in conditions like shock and heart failure{{cite journal | vauthors = Wenzl FA, Bruno F, Kraler S, Klingenberg R, Akhmedov A, Ministrini S, Santos K, Godly K, Godly J, Niederseer D, Manka R, Bergmann A, Camici GG, von Eckardstein A, Stähli B, Muller O, Roffi M, Räber L, Lüscher TF | title = Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes | journal = European Heart Journal | volume = 44 | issue = 38 | pages = 3859–3871 | date = October 2023 | pmid = 37632743 | doi = 10.1093/eurheartj/ehad545 }}{{cite journal | vauthors = Pöss J, Büttner P, Thiele H | title = Circulating dipeptidyl peptidase 3: new hope for a specific treatment to improve prognosis in cardiogenic shock? | journal = European Heart Journal | volume = 44 | issue = 38 | pages = 3872–3874 | date = October 2023 | pmid = 37632844 | doi = 10.1093/eurheartj/ehad568 }}{{cite journal | vauthors = Ye P, Duan W, Leng YQ, Wang YK, Tan X, Wang WZ | title = DPP3: From biomarker to therapeutic target of cardiovascular diseases | journal = Frontiers in Cardiovascular Medicine | volume = 9 | issue = | pages = 974035 | date = 2022 | pmid = 36312232 | pmc = 9605584 | doi = 10.3389/fcvm.2022.974035 | doi-access = free }}{{cite journal | vauthors = Méndez Hernández R, Ramasco Rueda F | title = Biomarkers as Prognostic Predictors and Therapeutic Guide in Critically Ill Patients: Clinical Evidence | journal = Journal of Personalized Medicine | volume = 13 | issue = 2 | date = February 2023 | page = 333 | pmid = 36836567 | pmc = 9965041 | doi = 10.3390/jpm13020333 | doi-access = free }}{{cite journal | vauthors = Blet A, Deniau B, Santos K, van Lier DP, Azibani F, Wittebole X, Chousterman BG, Gayat E, Hartmann O, Struck J, Bergmann A, Antonelli M, Beishuizen A, Constantin JM, Damoisel C, Deye N, Di Somma S, Dugernier T, François B, Gaudry S, Huberlant V, Lascarrou JB, Marx G, Mercier E, Oueslati H, Pickkers P, Sonneville R, Legrand M, Laterre PF, Mebazaa A | title = Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study | journal = Critical Care | volume = 25 | issue = 1 | article-number = 61 | date = February 2021 | pmid = 33588925 | pmc = 7885215 | doi = 10.1186/s13054-021-03471-2 | doi-access = free }}{{cite journal | vauthors = van Lier D, Beunders R, Kox M, Pickkers P | title = Associations of dipeptidyl-peptidase 3 with short-term outcome in a mixed admission ICU-cohort | journal = Journal of Critical Care | volume = 78 | issue = | article-number = 154383 | date = December 2023 | pmid = 37482013 | doi = 10.1016/j.jcrc.2023.154383 | doi-access = free }}{{cite journal | vauthors = Iborra-Egea O, Montero S, Bayes-Genis A | title = An outlook on biomarkers in cardiogenic shock | journal = Current Opinion in Critical Care | volume = 26 | issue = 4 | pages = 392–397 | date = August 2020 | pmid = 32452847 | doi = 10.1097/MCC.0000000000000739 }}

During shock, Angiotensin II production increases to restore blood pressure.{{cite journal | vauthors = Corrêa TD, Takala J, Jakob SM | title = Angiotensin II in septic shock | journal = Critical Care | volume = 19 | issue = 1 | article-number = 98 | date = March 2015 | pmid = 25886853 | pmc = 4360936 | doi = 10.1186/s13054-015-0802-3 | doi-access = free }} However, this compensatory mechanism is often impaired by factors such as myocardial infarction medications, endothelial dysfunction, and angiotensin-converting enzyme (ACE) dysfunction.{{cite journal | vauthors = Reynolds HR, Hochman JS | title = Cardiogenic shock: current concepts and improving outcomes | journal = Circulation | volume = 117 | issue = 5 | pages = 686–697 | date = February 2008 | pmid = 18250279 | doi = 10.1161/CIRCULATIONAHA.106.613596 }}{{cite journal | vauthors = Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hästbacka J, Khanna AK, Albertson TE, Tumlin J, Storey K, Handisides D, Tidmarsh GF, Chawla LS, Ostermann M | title = Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial | journal = American Journal of Respiratory and Critical Care Medicine | volume = 202 | issue = 9 | pages = 1253–1261 | date = November 2020 | pmid = 32609011 | pmc = 7605187 | doi = 10.1164/rccm.201911-2172OC }} Additionally, hypoperfusion and tissue death can elevate DPP3 levels in the blood, further compromising Ang II levels. This DPP3-dependent Ang II deficiency significantly exacerbate circulatory dysfunction in shock patients, perpetuating the shock spiral and ultimately leading to death.{{cite journal | vauthors = Picod A, Deniau B, Vaittinada Ayar P, Genest M, Julian N, Azibani F, Mebazaa A | title = Alteration of the Renin-Angiotensin-Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3 | journal = American Journal of Respiratory and Critical Care Medicine | volume = 203 | issue = 4 | pages = 526–527 | date = February 2021 | pmid = 33152252 | pmc = 7885828 | doi = 10.1164/rccm.202010-3873LE }}

DPP3 is the drug target of Procizumab, an anti-DPP3 antibody in clinical development by [http://www.4teen4.de 4TEEN4 Pharmaceuticals]. Procizumab is a humanized monoclonal antibody for the treatment of adult patients suffering from cardiogenic shock. Procizumab is designed to block the enzymatic activity of cDPP3 in the bloodstream, thereby inhibiting DPP3-dependent Ang II degradation. This blockade is intended to rapidly stabilize cardiovascular and renal functions, and therefore hemodynamics, and reduce mortality in affected patients. Inhibition of excess cDPP3 in the blood via procizumab has shown beneficial hemodynamic effects (improvement of cardiac and renal function), reduction of myocardial oxidative stress and improved survival in rodent models{{cite journal | vauthors = Deniau B, Blet A, Santos K, Vaittinada Ayar P, Genest M, Kästorf M, Sadoune M, de Sousa Jorge A, Samuel JL, Vodovar N, Bergmann A, Mebazaa A, Azibani F | title = Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study | journal = PLOS ONE | volume = 15 | issue = 8 | pages = e0238039 | date = 2020 | pmid = 32853284 | pmc = 7451654 | doi = 10.1371/journal.pone.0238039 | doi-access = free | bibcode = 2020PLoSO..1538039D | url = }} Procizumab studies in a large animal model of cardiovascular dysfunction showed that Procizumab-treated animals required lower doses of vasopressors and fluids to maintain adequate tissue perfusion and target mean arterial pressure (MAP) at 65 mmHg. These effects were associated with an increase in circulating Ang II concentrations, a preserved Ang I/Ang II ratio, prevention of ATIR downregulation and higher alpha-1, beta-1, and beta-2 adrenergic receptor expression. Reduction in catecholamine exposure by procizumab led to reduced inflammation and myocardial injury, exerting a cardioprotective effect. This aligns with the findings in rodents, where Procizumab administration reduces myocardial oxidative stress. Finally, Procizumab treatment also resulted in improved PaO2/FiO2 ratio (respiratory function). This positive effect on hypoxemia could be a better regional blood flow and distribution due to improved vascular tone caused by the normalized Ang II levels.

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• {{cite journal | vauthors = Fukasawa K, Fukasawa KM, Kanai M, Fujii S, Hirose J, Harada M | title = Dipeptidyl peptidase III is a zinc metallo-exopeptidase. Molecular cloning and expression | journal = The Biochemical Journal | volume = 329 ( Pt 2) | issue = Pt 2 | pages = 275–282 | date = January 1998 | pmid = 9425109 | pmc = 1219041 | doi = 10.1042/bj3290275 }}
• {{cite journal | vauthors = Simaga S, Babić D, Osmak M, Ilić-Forko J, Vitale L, Milicić D, Abramić M | title = Dipeptidyl peptidase III in malignant and non-malignant gynaecological tissue | journal = European Journal of Cancer | volume = 34 | issue = 3 | pages = 399–405 | date = February 1998 | pmid = 9640230 | doi = 10.1016/S0959-8049(97)00401-2 }}
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• {{cite journal | vauthors = Fukasawa K, Fukasawa KM, Iwamoto H, Hirose J, Harada M | title = The HELLGH motif of rat liver dipeptidyl peptidase III is involved in zinc coordination and the catalytic activity of the enzyme | journal = Biochemistry | volume = 38 | issue = 26 | pages = 8299–8303 | date = June 1999 | pmid = 10387075 | doi = 10.1021/bi9904959 }}
• {{cite journal | vauthors = Hashimoto J, Yamamoto Y, Kurosawa H, Nishimura K, Hazato T | title = Identification of dipeptidyl peptidase III in human neutrophils | journal = Biochemical and Biophysical Research Communications | volume = 273 | issue = 2 | pages = 393–397 | date = July 2000 | pmid = 10873616 | doi = 10.1006/bbrc.2000.2827 | bibcode = 2000BBRC..273..393H }}
• {{cite journal | vauthors = Abramić M, Schleuder D, Dolovcak L, Schröder W, Strupat K, Sagi D, Peter-Katalini J, Vitale L | title = Human and rat dipeptidyl peptidase III: biochemical and mass spectrometric arguments for similarities and differences | journal = Biological Chemistry | volume = 381 | issue = 12 | pages = 1233–1243 | date = December 2000 | pmid = 11209758 | doi = 10.1515/BC.2000.151 | s2cid = 22245963 }}

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• {{UCSC genome browser|DPP3}}
• {{UCSC gene details|DPP3}}