title: Pro-B-type natriuretic peptide-1-108 processing and degradation in human heart failure.
abstract: BACKGROUND
  We have reported that pro-B-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo.
  
  
  RESULTS
  We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminal-proBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF.
  
  
  CONCLUSIONS
  Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF.
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Huntley
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Sandberg
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Heublein
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
authors.forename: S Jeson
authors.initials: SJ
authors.lastname: Sangaralingham
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.affiliation: From the Cardiorenal Research Laboratory, Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN. Ichiki.tomoko@mayo.edu.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichiki
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; C524086:Pro-BNP1-108; D020097:Natriuretic Peptide, Brain
keywords: B-type natriuretic peptide; enzymes; heart failure