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.