Chromogranin-A production and fragmentation in patients with Takayasu arteritis

Abstract

Background: Chromogranin-A (CgA) is a secretory protein processed into peptides that regulate angiogenesis and vascular cells activation, migration and proliferation. These processes may influence arterial inflammation and remodelling in Takayasu arteritis (TA).

Methods: Plasma levels of full-length CgA (CgA439), CgA fragments lacking the C-terminal region (CgA-FRs) and the N-terminal fragment, CgA1-76 (vasostatin-1, VS-1) were analysed in 42 patients with TA and 20 healthy age-matched controls. Vascular remodelling was longitudinally assessed by imaging. CgA peptides were related to markers of systemic and local inflammation, disease activity and vascular remodelling.

Results: Levels of CgA-FRs and VS-1 were increased in TA. Treatment with proton-pump inhibitors (PPIs) and arterial hypertension partially accounted for CgA levels and high inter-patient variability. CgA439, CgA-FRs and VS-1 levels did not reflect disease activity or extent. Markers of systemic or local inflammation correlated with higher CgA-FRs and VS-1 in normotensive patients and with higher CgA439 in hypertensive patients. Treatment with non-biologic anti-rheumatic agents was associated with increased CgA-FRs and a distinctive regulation of CgA processing. Reduced blood levels of anti-angiogenic CgA peptides were associated with vascular remodelling in the groups of patients on PPIs and with arterial hypertension.

Conclusions: The plasma levels of CgA fragments are markedly increased in TA as a consequence of disease- and therapy-related variables. Anti-angiogenic forms of CgA may limit vascular remodelling. Given the effect of the various CgA peptides, it is advisable to limit the therapeutic prescriptions that might influence CgA-derived peptide levels to clearly agreed medical indications until further data become available.

Keywords: Biomarker; Chromogranin A; Proton-pump inhibitors; Takayasu arteritis; Vascular remodelling; Vasculitis.

Fig. 1

Levels of CgA-derived polypeptides in patients with TA. a Plasma concentrations of total CgA, obtained summing the concentration of the full-length molecule with that of the various CgA fragments in patients with TA and HCs (see “Methods”). ^***: significantly different from HCs, p ≤ 0.001. b Plasma concentrations of CgA₄₃₉, CgA-FRs and VS-1 in patients with TA and HCs. ^*** and ^*: significantly different from HCs, p ≤ 0.001 and p ≤ 0.05 respectively. c Plasma concentrations of CgA₄₃₉, CgA-FRs and VS-1 in TA patients with or without PPIs. ^***: significantly different from patients without PPIs, p ≤ 0.001. d Ratios of CgA₄₃₉, CgA-FRs and VS-1 to CgA_tot in TA patients with or without PPIs. e-f Plasma concentrations of CgA₄₃₉, CgA-FRs and VS-1 in normotensive versus hypertensive patients either in the whole group of TA patients (panel e) and in those on PPIs (panel f). ^*: significantly different from normotensive patients. AH arterial hypertension, CgA ₄₃₉ full-length chromogranin-A (residues 1–439), CgA-FRs, fragments of CgA spanning from the N-terminus to the central region but lacking the C-terminal region, CgA _tot total CgA, HC healthy controls, PPI proton-pump inhibitors, TA Takayasu arteritis, VS-1 vasostatin-1

Fig. 2

Levels of CgA peptides and selected TA clinical features. Plasma concentrations of CgA₄₃₉, CgA-FRs and VS-1 in the whole group of TA patients (left panels) and in those on PPI therapy (right panels), stratified for vascular enhancement (upper panels), disease activity (middle panels) and vascular progression (lower panels) (see “Methods”). CgA ₄₃₉ full-length chromogranin-A (residues 1–439), CgA-FRs fragments of CgA spanning from the N-terminus to the central region but lacking the C-terminal region, PPI proton-pump inhibitors, VS-1 vasostatin-1