Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling.

Abstract

A hallmark of heart failure (HF) is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we evaluate the efficacy of LOX inhibition to prevent adverse left ventricular (LV) remodeling and dysfunction using an experimental model of HF. Sprague-Dawley rats were subjected to surgically induced volume overload (VO) by creation of aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN; 100 mg/kg/day), was administered to rats with ACF or sham surgery at eight weeks postsurgery. Echocardiography was used to assess progressive alterations in cardiac ventricular structure and function. Left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, LV pressure and volume, and other indices of cardiac function. The LV ECM alterations were assessed by: (a) histological staining of collagen, (b) protein expression of collagen types I and III, (c) hydroxyproline assay, and (d) cross-linking assay. LOX inhibition attenuated VO-induced increases in cardiac stress, and attenuated increases in interstitial myocardial collagen, total collagen, and protein levels of collagens I and III. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats vs. untreated. Inhibition of LOX attenuated VO-induced decreases in LV stiffness and cardiac function. Overall, our data indicate that LOX inhibition was cardioprotective in the volume overloaded heart.