Cardiovascular disease (CVD) represents the leading cause of morbidity and mortality in the United States in both men and women. CVD also represents the greatest medical economic burden in the U.S. A hallmark of heart failure is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen-crosslinking enzyme, lysyl oxidase (LOX). Little is known about the regulation of LOX in the diseased heart, or how increased LOX activity promotes the progression to overt heart failure. In this study, we evaluate the efficacy of LOX inhibition to prevent cardiomyocyte detachment from the ECM, a phenomenon known as anoikis. This ultimately leads to cardiomyocyte apoptosis, programmed cell death. In our published findings and preliminary studies, Sprague-Dawley rats were subjected to surgically induced volume overload (VO) by creation of an aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN;100 mg/kg/d), was administered to rats with ACF or sham surgery at 8 weeks post-surgery. These rats had established ventricular remodeling and associated dysfunction caused by VO. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats versus untreated. We found that low inhibition reduced left ventricular (LV) collagen, and preliminary data indicate that this reduction was concomitant with a return to control levels of collagen I/III ratio. Further, the mechanisms underlying decreased cardiac function during disease were assessed by analyzing alterations in integrin expression. LOX inhibition attenuated VO-induced decreases in integrin expression. Altogether, these findings led us to hypothesize that inhibition of LOX confers cardioprotective effects by preventing the adverse ECM remodeling and decreased integrin expression that contributes to cardiomyocyte apoptosis, thereby maintaining systolic function and preventing heart failure. We will use an integrated approach to critically test this hypothesis by addressing the following specific aims: 1) will test the prediction that VO-stress induced increases in LOX activity promote progressive increases in cardiac fibrosis and 2) will test the prediction that decreased systolic function is a result of cardiomyocyte detachment, and subsequent apoptosis, resulting from decreased integrin expression and reduced myocyte adhesion to the ECM. Findings from the proposed studies will establish whether chronically increased cardiac LOX expression and activity promote adverse ECM alterations and cardiomyocyte apoptosis, thus accelerating the development of heart failure. Further, these studies may provide insight into novel therapies to target cardiac LOX for the regression of adverse ECM changes, dysfunction and heart failure.
This application for the NRSA research fellowship will provide a training opportunity for a future academic scientist. The studies proposed will first investigate the shift in integrin expression and ECM remodeling due to lysyl oxidase (LOX) over-activation in Sprague-Dawley rats with VO induced heart failure and then elucidate a possible treatment against heart disease by inhibiting LOX which has been shown to improve function.
| Ninh, Van K; El Hajj, Elia C; Mouton, Alan J et al. (2018) Chronic Ethanol Administration Prevents Compensatory Cardiac Hypertrophy in Pressure Overload. Alcohol Clin Exp Res : |
| El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K et al. (2017) Detrimental role of lysyl oxidase in cardiac remodeling. J Mol Cell Cardiol 109:17-26 |
