title: A plasma proteolysis pathway comprising blood coagulation proteases.
abstract: Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid β1-42 (Aβ1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes. Therefore, FXII and FVIIa serve as the sensor/initiator and executioner, respectively, for the proteolysis pathway. Moreover, activation of this pathway by one probe leads to the degradation of all three probes. Significant activation of this pathway follows tissue injury and may also occur in other disorders, e.g., Alzheimer's disease, of which Aβ1-42 is a key driver. However, enoxaparin, a clinically used anticoagulant, inhibits the proteolysis pathway and elevates plasma levels of the probes. Enoxaparin may also mitigate potential impact of activators of the proteolysis pathway on coagulation. Our results suggest that the proteolysis pathway is important for maintaining low levels of various plasma proteins. Our finding that enoxaparin inhibits this pathway provides a means to control it. Inhibition of this pathway may facilitate the development of disease biomarkers and protein therapeutics, e.g., plasma Aβ1-42 as a biomarker of Alzheimer's disease or recombinant human prolidase as an antitumor agent.
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Arup
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood; D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D005167:Factor VII / Q000235:genetics / Q000378:metabolism; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D006487:Hemostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood*; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005167:Factor VII; D005174:Factor XII; D010447:Peptide Hydrolases
keywords: Pathology Section; coagulation factor VII; coagulation factor XII; prolidase; proteolysis; amyloid β1-42