title: Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis.
abstract: Heart failure, the leading cause of hospitalization of elderly patients, is correlated with myocardial fibrosis (ie, deposition of excess extracellular matrix proteins such as collagen). A key regulator of collagen homeostasis is lysyl oxidase (LOX), an enzyme responsible for cross-linking collagen fibers. Our objective was to ameliorate age-related myocardial fibrosis by disrupting collagen cross-linking through inhibition of LOX. The nonreversible LOX inhibitor β-aminopropionitrile (BAPN) was administered by osmotic minipump to 38-week-old C57BL/6J male mice for 2 weeks. Sirius Red staining of myocardial cross sections revealed a reduction in fibrosis, compared with age-matched controls (5.84 ± 0.30% versus 10.17 ± 1.34%) (P < 0.05), to a level similar to that of young mice at 8 weeks (4.9 ± 1.2%). BAPN significantly reduced COL1A1 mRNA, compared with age-matched mice (3.5 ± 0.3-fold versus 15.2 ± 4.9-fold) (P < 0.05), suggesting that LOX is involved in regulation of collagen synthesis. In accord, fibrotic factor mRNA expression was reduced after BAPN. There was also a novel increase in Ly6C expression by resident macrophages. By interrupting collagen cross-linking by LOX, the BAPN treatment reduced myocardial fibrosis. A novel observation is that BAPN treatment modulated the transforming growth factor-β pathway, collagen synthesis, and the resident macrophage population. This is especially valuable in terms of potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Rosin
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Mryanda J
authors.initials: MJ
authors.lastname: Sopel
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Alec
authors.initials: A
authors.lastname: Falkenham
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Timothy D G
authors.initials: TD
authors.lastname: Lee
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address: jean.legare@cdha.nshealth.ca.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Légaré
mesh_terms: D000367:Age Factors; D000629:Aminopropionitrile / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D000629:Aminopropionitrile; D003094:Collagen