DPP3

Dipeptidyl-peptidase 3 is an enzyme that in humans is encoded by the DPP3 gene.

This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. This cytoplasmic protein binds a single zinc ion with its zinc-binding motif (HELLGH) and has post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Increased activity of this protein is associated with endometrial and ovarian cancers. Alternate transcriptional splice variants have been characterized.

Dipeptidyl-peptidase 3 has been found to act as a myocardial depressant factor. Procizumab, a specific antibody for dipeptidyl-peptidase 3, was found to improve cardiac and renal function in a mouse model of heart failure. In human studies, higher levels of circulating DPP3 protein in cardiogenic shock patients indicated a more severe disease course, with a higher risk of refractory cardiogenic shock and death.

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. 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.

DPP3 degrades a variety of bioactive peptides, including angiotensins and endogenous opioids like enkephalins and endomorphins 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. 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.

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.

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. Consequently, DPP3 knockout mice exhibit sustained oxidative stress, disrupted bone homeostasis, and dysregulation of the renin-angiotensin-aldosterone system (RAAS) peptides in the blood. 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

During shock, Angiotensin II production increases to restore blood pressure. However, this compensatory mechanism is often impaired by factors such as myocardial infarction medications, endothelial dysfunction, and angiotensin-converting enzyme (ACE) dysfunction. 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.

DPP3 is the drug target of Procizumab, an anti-DPP3 antibody in clinical development by 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 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.

• DPP3 human gene location in the UCSC Genome Browser.
• DPP3 human gene details in the UCSC Genome Browser.