Inhibition of lysyl oxidase activity reverses fibrosis and improves cardiac function (1152.8)

Abstract

The collagen crosslinking enzyme, lysyl oxidase (LOX), is elevated in human dilated cardiomyopathy and heart failure, but it is not known if LOX plays a causative role in disease. However, clinical evidence shows that diuretics with LOX inhibitory properties are more effective at slowing the progression of heart failure. Using the aortocaval fistula (ACF) rat model of volume overload, we assessed the efficacy of LOX inhibition to reverse cardiac fibrosis and dysfunction in rodents with established cardiac disease. Serial echocardiography was used to evaluate cardiac structural and functional changes. LOX inhibition (100 mg/kg/d BAPN; osmotic minipumps) was initiated 8 wks post‐surgery in ACF and SHAM‐operated rats. Treatment continued for 6 wks and hearts were collected for analysis. Left ventricular (LV) sections were stained with PSR for collagen volume fraction (CVF). Protein expression was assessed in LV homogenates by WB. Untreated ACF had significantly increased LV LOX expression (65% increase), concomitant with LV dilatation (43% increase), depressed fractional shortening (26% decrease), increased collagen cross‐linking (52% increase), and interstitial fibrosis (CVF; 135% increase) relative to SHAM (p<0.05). LOX inhibition reversed fibrosis (CVF; Treated ACF vs SHAM; p=NS) and partially restored cardiac function (20% increase vs Untreated ACF). However, there was no significant reversal of LV hypertrophy or dilatation. LV NADPH oxidase‐4 was increased in untreated ACF (52% increase vs SHAM), but was not different in treated ACF, indicating a possible role for oxidative stress in the observed beneficial effects of LOX inhibition. These data identify inhibition of LOX activity as a potential therapeutic approach for the regression of cardiac fibrosis and improvement of function in heart failure patients. Grant Funding Source: Supported by LSUSOM REF grant (jdg) and the American Heart Association GSA 11GRNT7700002 (jdg)