期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 185, 期 3, 页码 631-642出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2014.11.009
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资金
- Canadian Institutes of Health Research [CHR116835]
- Heart and Stroke Foundation of Nova Scotia
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 beta-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 parts per thousand 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 C0L1A1 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-beta 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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