Inhibition of Lysyl Oxidase Activity Prevents Volume Overload Diastolic and Systolic Dysfunction
Authors: El Hajj Elia C. , El Hajj Milad C. , Ninh Van K. , Gardner Jason D. 
Published: June 2021

The cardiac extracellular matrix (ECM) is a structural framework which bridges cardiomyocytes to the cystoskeletal myofibril, preserving alignment, while providing tensile strength to the myocardium. Abnormalities in the architectural scaffolding of the ECM have been noted during various cardiac pathologies. The major structural components of the cardiac ECM are collagens, which are produced by fibroblasts. The relative expression of collagens and the degree of cross‐linking dictate the passive mechanical properties of the heart. Lysyl oxidase (LOX) is a copper‐dependent amine oxidase that plays a critical role in covalently cross‐linking fibrillar collagens, which determines the insolubility, stiffness and resistance to degradation of the resulting collagen fibrils. In our previous studies we have shown marked increases in LOX expression and activity in failing hearts relative to compensated and unstressed hearts. Our goal of this study was to determine whether LOX inhibition, initiated during the early stages of cardiac remodeling, could attenuate fibrosis and cardiac dysfunction.

We used the aortocaval fistula (ACF) surgical model on Sprague‐Dawley rats to induce biventricular volume overload (VO). Two weeks after surgery, both sham‐operated and VO rats were treated with the LOX inhibitor, beta‐aminoproprionitrile (BAPN; 100 mg/kg/d), for 12 weeks. BAPN was administered via an osmotic pump surgically inserted into the abdominal cavity. After a total of 14 weeks of VO, left ventricular (LV) pressure‐volume catheterization was used to assess alterations in cardiac function. Western blot protein analyses were performed to assess alterations in LOX, collagens I and III, matrix metalloproteinases (MMPs), and their inhibitors (TIMPs). Further, LV strain and stiffness were calculated to determine alterations in diastolic function.

Our data demonstrate that chronic VO caused a significant increase in LV wall stress at both diastole and systole, and produced significant LV hypertrophy (183%, 60%, and 92% increase, respectively vs. control; p<0.05). Further, VO induced significant increases in LV strain and stiffness (126% and 77% increase, respectively vs. control), as well as significant increases in the expression of fibrotic proteins including LOX, collagen I, collagen III, MMP2, and TIMP1 (135%, 58.4%, 26.7%, 39%, and 63% increase, respectively vs. control; p<0.05). Finally, VO also caused systolic dysfunction, as evident by decreases in cardiac contractility and ejection fraction (51% and 26% decrease, respectively vs. control; p<0.05). Further, our data highlight the cardioprotective role of LOX inhibition against adverse cardiac remodeling due to VO. LOX inhibition completely prevented VO‐induced increases in LV wall stress and ventricular hypertrophy. Further, LOX inhibition prevented VO‐induced fibrosis and diastolic dysfunction, as evident by normalized levels of collagens, LOX, MMPs, TIMPs, and LV stiffness. Finally, LOX inhibition prevented the VO‐induced decline in cardiac contractility. Overall, our data indicate that LOX inhibition prevented adverse ECM remodeling and cardiac dysfunction in the volume overloaded heart.

Support or Funding Information

Support for this project provided by the American Heart Association Southeast Affiliate and the NIH Heart, Lung and Blood Institute: Grant‐in‐Aid (#16GRNT30440008‐JDG), AHA Predoctoral Fellowship (# 16PRE29150010‐EEH), and F31 (#1F31HL134263‐ 01A1‐EEH).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.