Neprilysin Function and Cardiovascular Health

Neprilysin is a ubiquitous zinc-dependent endopeptidase that regulates the homeostasis of key vasoactive peptides, notably natriuretic peptides, bradykinin and adrenomedullin. By cleaving these substrates, neprilysin influences vasodilation, natriuresis and inhibition of fibrosis, thereby modulating blood pressure and cardiac remodelling. In healthy physiology, a balance between neprilysin activity and peptide secretion maintains vascular resistance and fluid volume. In heart failure, elevated levels of natriuretic peptides reflect compensatory mechanisms to counteract reduced cardiac output, yet excessive neprilysin activity can degrade these protective peptides and exacerbate haemodynamic stress. Conversely, evidence has emerged that membrane-bound neprilysin on immune cells, notably neutrophils, may have distinct local functions in inflammation and extracellular matrix turnover. Pharmacological inhibition of neprilysin, combined with angiotensin receptor blockade, has demonstrated substantial improvements in morbidity and mortality in patients with reduced ejection fraction, underscoring the therapeutic potential of modulating neprilysin. Ongoing research seeks to refine patient selection through measurement of circulating neprilysin forms, to understand the enzyme’s role in heart failure with preserved ejection fraction, and to identify tissue-specific effects that may extend benefits to kidney disease and post-infarction remodelling.

Research from Nature Portfolio

Analyses of treatment-naïve cancer cohorts have clarified that circulating neprilysin levels show only weak inverse correlations with age and inflammatory markers, and do not reliably reflect established cardiac biomarkers or predict overall survival, indicating limited utility of soluble measurements in mixed-disease populations. A complementary investigation in outpatients with chronic heart failure revealed that higher soluble neprilysin levels are independently associated with an increased rate of hospital admissions for heart failure in overweight women, whereas no similar prognostic effect was observed in men or in women with lower body mass index. These findings underscore a complex interplay between sex, adiposity and neprilysin biology that may inform personalised risk stratification in heart failure management.

Neprilysin Function and Cardiovascular Health publication trend

The graph below shows the total number of articles in neprilysin function and cardiovascular health across all publications each year (not limited to Nature Index journals).

Technical terms

Neprilysin: A zinc-dependent metalloprotease that degrades vasoactive peptides and regulates vascular tone and fluid balance.

Soluble neprilysin (sNEP): The circulating form of neprilysin found in plasma, reflecting extracellular enzyme activity.

Neutrophil membrane neprilysin (mNEP): The transmembrane form of neprilysin on neutrophils, implicated in inflammation and extracellular matrix modulation.

Heart failure with reduced ejection fraction (HFrEF): A clinical syndrome in which left ventricular ejection fraction falls below 40%, leading to compromised cardiac output.

Left ventricular ejection fraction (LVEF): The percentage of blood ejected from the left ventricle with each heartbeat, a key index of pump function.

References

1. The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients. Scientific Reports (2019).
2. The influence of sex and body mass index on the association between soluble neprilysin and risk of heart failure hospitalizations. Scientific Reports (2021).
3. Relevance of Neutrophil Neprilysin in Heart Failure. Cells (2021).
4. Circulating Neprilysin Level Predicts the Risk of Cardiovascular Events in Hemodialysis Patients. Frontiers in Cardiovascular Medicine (2021).
5. Soluble neprilysin and long-term clinical outcomes in patients with coronary artery disease undergoing percutaneous coronary intervention: a retrospective cohort study. BMC Cardiovascular Disorders (2020).