Physiologic inhibition of human activated protein C by alpha 1-antitrypsin.
The plasma antithrombotic enzyme activated protein C (APC) has two major plasma inhibitors. One is heparin-dependent, has been characterized, and is known as protein C inhibitor. The second inhibitor was isolated based on its heparin-independent ability to inhibit and complex with APC. The purified inhibitor had the amino acid composition and NH2 terminus of alpha 1-antitrypsin and reacted with monoclonal antibodies to alpha 1-antitrypsin. The inhibitor was greater than 95% pure alpha 1-antitrypsin as judged by electroimmunoassay, inactivation of trypsin, and electrophoresis in two gel systems. To identify the second major plasma inhibitor of APC, immunoblot studies of enzyme-inhibitor complexes were made to compare APC addition to normal plasma and to plasma deficient in protein C inhibitor or alpha 1-antitrypsin. The results showed that alpha 1-antitrypsin is the second major plasma APC inhibitor. Given the association rate constant of alpha 1-antitrypsin for APC of 10 M-1 s-1 and its plasma concentration of approximately 40 microM, it accounts for approximately half of the heparin-independent APC inhibitory activity of plasma. Based on immunoblot analysis plasmas of 15 patients with intravascular coagulation contained APC-alpha 1-antitrypsin complexes suggesting that this inhibition reaction occurs in vivo. Thus, alpha 1-antitrypsin is a major physiologic inhibitor of APC.
Heeb
M J
MJ
Research Institute, Scripps Clinic, La Jolla, California 92037.
Griffin
J H
JH
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D004211:Disseminated Intravascular Coagulation / Q000097:blood; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007118:Immunoassay; D008969:Molecular Sequence Data; D008970:Molecular Weight; D011486:Protein C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*
D000596:Amino Acids; D011486:Protein C; D000515:alpha 1-Antitrypsin