Lysyl oxidase inhibition in the volume overloaded heart prevents adverse collagen remodeling, apoptosis, and cardiac dysfunction

Abstract

Heart failure is the most prevalent and costly disease in the U.S. Our goal was to determine if the over‐activation of lysyl oxidase (LOX), a collagen cross‐linking enzyme, accelerates cardiac disease and failure. LOX is elevated in human failing hearts, but it is not known if LOX plays a causative role in disease. Using the aortocaval fistula (ACF) rat surgical model of volume overload, we assessed the role of LOX activity in progression of heart failure over 14 wks. LOX activity was inhibited by BAPN (100 mg/kg/d) at 2 wks post‐surgery. Echocardiography was used to evaluate cardiac function and progression of LV remodeling. LOX expression and activity, collagen content, cross‐linking, and typing were determined in LV homogenates. Fixed sections of mid‐LV were assessed for apoptosis by TUNEL. ACF surgery caused significant ventricular dilatation (43% increase) and dysfunction (26% decreased, %FS). LOX protein expression was increased (65%) with concomitant increases in LOX activity. These increases in LOX were associated with significantly elevated collagen concentration, cross‐linking, and type I/III. LOX inhibition prevented ACF‐induced changes in LV collagen, and led to maintenance of systolic function. LOX inhibition also attenuated LV dilatation and prevented apoptosis, but did not reduce LV hypertrophy. These data indicate that LOX inhibition is cardioprotective in the volume overloaded heart.