Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein

Abstract

The plasma concentration of the placentally derived proMBP (proform of eosinophil major basic protein) increases in pregnancy, and three different complexes containing proMBP have been isolated from pregnancy plasma and serum: a 2:2 complex with the metalloproteinase, PAPP-A (pregnancy-associated plasma protein-A), a 2:2 complex with AGT (angiotensinogen) and a 2:2:2 complex with AGT and complement C3dg. In the present study we show that during human pregnancy, all of the circulating proMBP exists in covalent complexes, bound to either PAPP-A or AGT. We also show that the proMBP-AGT complex constitutes the major fraction of circulating HMW (high-molecular weight) AGT in late pregnancy, and that this complex is able to further associate with complement C3 derivatives post-sampling. Clearance experiments in mice suggest that complement C3-based complexes are removed faster from the circulation compared to monomeric AGT and the proMBP-AGT complex. Furthermore, we have used recombinant proteins to analyse the formation of the proMBP-PAPP-A and the proMBP-AGT complexes, and we demonstrate that they are competing reactions, depending on the same cysteine residue of proMBP, but differentially on the redox potential, potentially important for the relative amounts of the complexes in vivo. These findings may be important physiologically, since the biochemical properties of the proteins change as a consequence of complex formation.

PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

“…The immunoassay for PAPP-A does not allow for distinction between enzymatically active PAPP-A, which corresponds to free, dimeric PAPP-A, and enzymatically inactive PAPP-A composed of dimeric PAPP-A covalently linked to two molecules of eosinophil major basic protein (proMBP) [ 18 , 19 ]. Therefore, the enzymatic activity of PAPP-A in ascites was determined by measuring the total concentration of PAPP-A and the concentration of PAPP-A/proMBP complex [ 20 ]. PAPP-A activity was then expressed as the fraction of PAPP-A not complexed to proMBP.…”

Endocrine aspects of pre-eclampsia

“…This is a complex of angiotensinogen with proMBP (proform of eosinophil major basic protein) and its cleavage by renin is markedly altered, a fact that may explain the reduced plasma renin activity described in pre-eclampsia [35]. In addition, Zhou and colleagues [36] have recently described two isoforms of angiotensinogen with either reduced or oxidized forms of a disulphide bridge in the molecule.…”

40 YEARS OF IGF1: PAPP-A and cancer

“…It may be speculated that proMBP functions to protect tissues other than the placenta from excessive PAPP-A and IGF activity during human pregnancy. How the degree of complex formation is regulated is unknown (Kloverpris et al 2013).…”