title: The aging heart, myocardial fibrosis, and its relationship to circulating C-type natriuretic Peptide.
abstract: Myocardial aging is characterized by left ventricular (LV) fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent antifibrotic and antiproliferative properties of C-type natriuretic peptide (CNP); however, the relationship between circulating CNP, LV fibrosis, and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2-, 11-, and 20-month-old male Fischer rats. Further in vitro, we established the antiproliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis that precedes impairment of diastolic and systolic function. Additionally, we demonstrate in cultured adult human cardiac fibroblasts that the direct antiproliferative actions of high-dose CNP may involve a non-cGMP pathway via the clearance receptor. Together, these studies provide new insights into myocardial aging and the relationship to the antifibrotic and antiproliferative peptide CNP.
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA. sangaralingham.jeson@mayo.edu
authors.forename: S Jeson
authors.initials: SJ
authors.lastname: Sangaralingham
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Huntley
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Martin
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKie
authors.forename: Diego
authors.initials: D
authors.lastname: Bellavia
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichiki
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Harders
authors.forename: Horng H
authors.initials: HH
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000328:Adult; D000375:Aging; D000818:Animals; D001794:Blood Pressure; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005355:Fibrosis / Q000097:blood; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type