Xanthine oxidase inhibition and heart failure: novel therapeutic strategy for ventricular dysfunction?

Myocardial dysfunction and heart failure perturb cardiovascular homeostatic signaling pathways as well as initiate a program of molecular, biochemical, and structural modifications to remodel the failing ventricle. Accumulating evidence suggests that the cardiovascular redox state plays an integral role in these processes. In fact, in the failing heart, elevated levels of reactive oxygen species (ROS) and cardiomyocyte oxidant stress are associated with maladaptive ventricular remodeling and a progressive decline in cardiovascular function. The association between ROS and heart failure has been established. Increased indices of oxidant stress have been measured in patients with congestive heart failure. In clinical studies, patients with heart failure were found to have evidence of lipid peroxidation and elevated 8-iso-prostaglandin F2 levels1–4 whereas in experimental models of heart failure, investigators have been able to directly measure increased ROS production from cardiomyocytes.5,6 These findings have been corroborated in studies that measured ROS levels in explanted human hearts at the time of transplant.7 Furthermore, a number of neurohormonal and mechanical stressors that are associated with the heart failure phenotype augment ROS generation.8,9 Prolonged exposure to ROS, in turn, results in cardiomyocyte dysfunction.10 At a cellular level, elevated levels of ROS impair cardiomyocyte function by damaging ion channels as well as inhibiting contractility. ROS disrupt the structural integrity of ion channels via membrane lipid peroxidation.2,11 ROS also decrease expression and activity of the sarcoplasmic reticulum Ca ATPase SERCA2,12 which is critical for effective cardiac calcium handling. Interestingly, ROS have also been shown to decrease myofilament calcium sensitivity by activation of ASK-1, a redox-sensitive kinase. ASK-1 phosphorylates troponin T and thereby decreases contractility and regulates calcium handling.13 Concomitant with these adverse effects on cardiomyocyte function, ROS stimulates a number of responses associated with the ventricular remodeling processes. These include ROS-mediated activation of matrix metalloproteinases to alter the architecture of the extracellular matrix,14 modulation of signal transduction pathways that initiate cardiomyocyte hypertrophy,15 and apoptosis or cell death.16 Taken together, these observations suggest that one mechanism to halt deleterious ventricular remodeling and abnormal cardiomyocyte functional responses is to decrease oxidant stress by limiting ROS production. ROS are derived from the superoxide anion, a one-electron reduction product of oxygen. In the myocardium, superoxide anion may be generated by both metabolic and enzymatic sources including mitochondrial respiration, xanthine oxidase (XO), NAD(P)H oxidases, and, when substrate or cofactors are not replete, uncoupled nitric oxide synthase(s).17,18 In the failing heart, activation of these ROS-generating systems leads to the accumulation of superoxide anions and the formation of a number of pathophysiologically relevant reactive species including hydrogen and lipid peroxides, peroxynitrites, and peroxynitrous acids. In the failing heart, there is experimental evidence to suggest that xanthine oxidoreductase (XOR), comprised of the isoenzymes XO and xanthine dehydrogenase (XDH), is an important source of ROS. Xanthine oxidase catalyzes the terminal steps in the catabolism of purines to uric acid in a series of reactions that reduce molecular oxygen to yield superoxide.18 Studies have shown that XO expression, as well as activity, are increased in cardiomyocytes isolated from failing hearts.19–22 In contrast, inhibition of XO activity with allopurinol or oxypurinol in rodent or canine heart failure models improved myocardial function, decreased myocardial oxygen consumption, and ameliorated myocardial contractility.19 Although it was not shown conclusively that these effects resulted from inhibition of XO-generated ROS, other studies done with antioxidant agents suggest that this may be the case. Here it was found that treatment with high doses of the antioxidant ascorbate resulted in the same benefits that were seen with allopurinol.20 Prolonged inhibition of XO with allopurinol in rodent models of post-infarction heart failure has also been shown to prolong survival, improve contractile function, and prevent ventricular remodeling.21,23 These effects are believed to result from allopurinol-mediated XO inhibition and a resultant decrease in ROS levels. In this issue of Circulation Research, Minhas et al extend these findings and demonstrate that XO inhibition initiates reverse remodeling in rats with established dilated cardiomyopathy.24 In these studies, the authors used a rat model of heart failure, the spontaneously hypertensive/Heart Failure (SHHF) model and inhibited XO with oxypurinol. Treatment of SHHF rats with oxypurinol decreased ROS levels and improved hemodynamic and contractile parameters in vivo. In addition, oxypurinol abrogated (1) fetal gene activation, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology at Massachusetts General Hospital (R.J.H.) and the Cardiology Division, Department of Medicine, Brigham & Women’s Hospital (J.A.L.), Harvard Medical School, Boston, Mass. Correspondence to Roger J. Hajjar MD, Massachusetts General Hospital, Cardiovascular Research Center, 149 13 Street, Room 4215, Charlestown, MA 02129. E-mail [email protected] (Circ Res. 2006;98:169–171.) © 2006 American Heart Association, Inc.