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Role of Cysteine Residues in Human Angiotensinogen

The M235T polymorphism of human angiotensinogen is associated with essential and pregnancy-induced hypertension. A covalent complex is formed between angiotensinogen and the proform of the eosinophil major basic protein (proMBP) during pregnancy. The sequence of human angiotensinogen contains four cysteines. Their function was analyzed. Presence of free cysteines was demonstrated by their alkylation with iodo[14C]acetic acid. A disulfide bond between Cys18 and Cys138 using a fully N-deglycosylated mutant of human angiotensinogen was identified by tryptic digestion and mass spectrometry. We produced angiotensinogen· proMBP complex by co-transfection of COS-7 cells and by co-culturing transfected CHO-K1 cells. Experiments with 8 mutated recombinant angiotensinogen, in which one or more of the four cysteines were replaced by alanine, demonstrated that Cys232 is involved in complex formation and could interact with the M235T variant. The angiotensinogen·proMBP complex was isolated by molecular sieving. Hydrolysis of the complex by human renin was 7 times slower than hydrolysis of monomeric form, whatever the M235T genotype. The complex:monomeric angiotensinogen ratio was greater for Met235 (72%) than for Thr235 (58%) angiotensinogen. These data suggest a new pathophysiological explanation for the genetic association between M235T angiotensinogen polymorphism and pregnancy-induced hypertension.