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Published on: June 14, 2016
Disruption of collagen homeostasis can reverse established age-related myocardial fibrosis
Nicole L Rosin1, Mryanda J Sopel1, Alec Falkenham1
1Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Insights
Inhibiting lysyl oxidase (LOX) with BAPN reduced age-related myocardial fibrosis in mice by disrupting collagen cross-linking. This novel approach also modulated fibrotic pathways and macrophage populations, offering potential therapeutic strategies.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Pharmacology
Background:
- Heart failure, a major cause of hospitalization in the elderly, is linked to myocardial fibrosis.
- Myocardial fibrosis involves the excessive deposition of collagen, a process regulated by lysyl oxidase (LOX).
- Lysyl oxidase (LOX) is crucial for cross-linking collagen fibers, impacting tissue structure and function.
Purpose of the Study:
- To investigate the potential of inhibiting lysyl oxidase (LOX) to reduce age-related myocardial fibrosis.
- To determine if disrupting collagen cross-linking can ameliorate cardiac fibrosis in aged mice.
- To explore the effects of LOX inhibition on collagen synthesis and related fibrotic pathways.
Main Methods:
- Administration of a nonreversible lysyl oxidase (LOX) inhibitor, β-aminopropionitrile (BAPN), to aged male C57BL/6J mice for two weeks.
- Quantification of myocardial fibrosis using Sirius Red staining.
- Analysis of collagen type 1 alpha 1 (COL1A1) mRNA expression and other fibrotic factor mRNA levels.
Main Results:
- BAPN treatment significantly reduced myocardial fibrosis in aged mice compared to controls.
- Fibrosis levels in BAPN-treated mice were comparable to those in young mice.
- BAPN administration led to a significant decrease in COL1A1 mRNA expression, indicating reduced collagen synthesis.
- Reduced expression of other fibrotic factors and a novel increase in Ly6C expression by resident macrophages were observed.
Conclusions:
- Interruption of collagen cross-linking via lysyl oxidase (LOX) inhibition effectively reduces age-related myocardial fibrosis.
- BAPN treatment modulates the transforming growth factor-β pathway, collagen synthesis, and resident macrophage populations.
- Targeting collagen regulation through LOX inhibition presents a promising therapeutic strategy for 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.
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