August 4, 2021Open Access
Novel insights into peptide amidation and amidating activity in the human circulation
Structured PICO
Does increased serum PAM amidating activity predict cardiovascular mortality, heart failure, and atrial fibrillation in a general population cohort?
P
Population
4,942 individuals from a random sub-cohort of the Malmoe Preventive Project (MPP) for the observational study, and rats for the in vivo experimental study.
I
Intervention
Measurement of serum PAM amidating activity (AMA) using a novel assay in humans; intravenous injection of recombinant human PAM, ascorbate, or both in rats.
C
Comparator
Lowest quartile of PAM-AMA (Q1) for the human cohort; placebo injection for the rat study.
O
Outcome
All-cause mortality, cardiovascular mortality, incident heart failure, and incident atrial fibrillation during an average follow-up of 8.8 ± 2.5 years.hard clinical
Serum PAM amidating activity is an independent predictor of cardiovascular mortality, heart failure, and atrial fibrillation, suggesting its potential as a novel biomarker for hemodynamic stress.
Abstract
C-terminal α-amidation is the final and essential step in the biosynthesis of several peptide hormones. Peptidylglycine α-amidating monooxygenase (PAM) is the only known enzyme to catalyse this reaction. PAM amidating activity (AMA) is known to be present in human circulation, but its physiological role and significance as a clinical biomarker remains unclear. We developed a PAM-specific amidation assay that utilizes the naturally occurring substrate Adrenomedullin-Gly (ADM-Gly, 1-53). Using our amidation assay we quantified serum amidating activities in a large population-based cohort of more than 4900 individuals. A correlation of serum amidating activity with several clinical parameters including high blood pressure was observed. Increasing PAM-AMA was an independent predictor of hard outcomes related to hemodynamic stress such as cardiovascular mortality, atrial fibrillation and heart failure during long-term follow-up (8.8 ± 2.5 years). Moreover, results from an animal study in rats utilizing recombinant human PAM provide novel insights into the physiological role of circulating PAM and show its potential significance in circulating peptide amidation.