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Cardioprotective Effects of Lysyl Oxidase Inhibition Against Adverse Extracellular Matrix Remodeling and Cardiomyocyte Apoptosis
Author(s) -
El Hajj Elia C,
El Hajj Milad C,
Ninh Van K,
Mouton Alan J,
Gardner Jason D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.881.5
Subject(s) - lysyl oxidase , extracellular matrix , heart failure , ventricular remodeling , fibrosis , medicine , cardiac function curve , myocyte , contractility , endocrinology , chemistry , microbiology and biotechnology , biology
The heart's size, shape, and function are regulated by a dynamic interaction between cardiac myocytes and the extracellular matrix (ECM). The major structural component of the cardiac ECM is collagen, which is produced by fibroblasts. Lysyl oxidase (LOX), also produced by fibroblasts, is a collagen cross‐linking enzyme and is significantly elevated in failing human hearts. However, little is known about how increased LOX activity may promote the progression to overt heart failure; and how adverse ECM remodeling can contribute to cardiomyocyte detachment from the ECM, a phenomenon known as anoikis, and subsequent cell death. Our goal for this study was to determine if inhibition of LOX, in rodents with established cardiac disease, would limit the adverse ECM changes and subsequent cardiomyocyte death, thus preventing the progression to heart failure. The aortocaval fistula rat surgical model of volume overload (VO) was used. Eight weeks after surgery, both sham‐operated and VO rats were treated with the LOX inhibitor, beta‐aminopropionitrile (BAPN; 100 mg/kg/d) for six weeks. At 14 weeks, left ventricular (LV) catheterization was used to assess alterations in contractility and cardiac function. Picrosirius red was used to measure interstitial myocardial collagen. Western Blotting was used to measure protein expression of collagens I and III, integrins alpha 3 and 5, caspases 3 and 9, and bax/bcl2. Cell cultures were used to assess the adherence and viability of freshly isolated cardiac myocytes to control and VO fibroblasts. VO induced significant LV hypertrophy (116% increase vs sham), fibrosis (172%, 77% and 22% increase in interstitial myocardial collagen, collagen I and collagen III, respectively vs sham), and cardiac dysfunction (17% decrease vs sham). VO induced significant decreases in the integrins alpha 3 and alpha 5 (10% and 21% decrease, respectively vs sham), indicative of decreased adhesion. VO also induced significant increases in caspase 3, caspase 9 and bax/bcl2 ratio (11%, 25%, and 15% increase, respectively vs sham), indicative of increased cellular apoptosis. Finally, we observed decreased viability of myocytes co‐cultured with VO‐fibroblasts vs control fibroblasts. LOX inhibition partially attenuated VO‐induced increases in LV hypertrophy (23% decrease vs VO) and completely attenuated VO‐induced increases in interstitial myocardial collagen, and protein expression of collagens I and III compared to VO. LOX inhibition conferred cardioprotective effects as shown via improved ejection fraction and improved contractility (9% and 70% increase, respectively vs VO). Further LOX inhibition completely attenuated VO‐induced decreases in alpha 3 and alpha 5 integrins. Finally, LOX inhibition partially attenuated VO‐induced increases in caspase 3, caspase 9 and bax/bcl2 ratio (13%, 18% and 15% decrease, respectively vs VO), indicative increased cell viability. Next, we plan to assess the effects of the LOX inhibitor on myocyte viability in co‐cultures. Overall, our data demonstrate the cardioprotective effects of LOX inhibition against adverse ECM remodeling, as well as cardiomyocyte detachment and death. Support or Funding Information Funded by the American Heart Association Greater Southeast Affiliate #16GRNT30440008 (JG) Pre‐doctoral Fellowship #16PRE29150010 (EEH)Working hypothesis of LOX‐induced cardiac remodeling and dysfunction.