Xanthine Oxidase Contributes to Mitochondrial ROS Generation in an Experimental Model of Cocaine-Induced Diastolic Dysfunction

Abstract

Recent studies have shown that long-term cocaine use induces diastolic impairment and a myocardial oxidative stress. Recently, we have reported that cocaine-induced cardiac dysfunction may be due to a mitochondrial reactive oxygen species (ROS) overproduction, which occurs at the same time as xanthine oxidase (XO) activation. In this work, we hypothesized that XO activation contributes to mitochondrial ROS overproduction, which in turn contributes to diastolic dysfunction. To test this, we used a well-established in vivo model of cocaine-induced diastolic dysfunction. In this experimental model treated with or without allopurinol, an inhibitor of XO, we measured mitochondrial ROS production and function. Mitochondrial alterations were characterized by an increase in oxygen consumption through complexes I and III, a reduction in ATP production, and an increased ROS production specifically in isolated interfibrillar mitochondria. Allopurinol treatment prevented the rise in mitochondrial ROS levels and the decrease in ATP production. In the same way, allopurinol treatment improved ventricular relaxation with a decrease in Tau, an index of left ventricle relaxation and of end-diastolic pressure volume relation. These results confirmed the critical role of XO in the sequence of events leading to cocaine-induced cardiac dysfunction.

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

“…These authors conclude that the reduced synthesis rate of mitochondrial proteins in response to ethanol exposure may be partly connected to depression in myocardial contractility and associated with functional damage of mitochondrial metabolism (120). In contrast, cocaine-induced cardiac dysfunction in rats revealed increased ROS production and decreased ATP synthesis in the IFM (137), which may occur through a xanthine oxidase-mediated mechanism (138). Hence, the majority of studies investigating the effects of drugs on mitochondrial subpopulations implicate SSM as being primarily affected.…”

Cardiovascular consequences of cocaine use

“…[20]. Further amplification of this oxidative stress cycle occurs via ROS-induced ROS release by cardiomyocyte mitochondria [21,22] and inhibition of cardiac antioxidant systems [18]. In a rat model of cocaine-induced cardiac dysfunction, Vergeade et al [21] demonstrated complete prevention of cardiac dysfunction following cocaine administration in rats that were also treated with MitoQ, a mitochondrial-targeted antioxidant.…”

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

“…One of the key mediators in ligandindependent transactivation of growth factor receptors, including PDGFR, are reactive oxygen species (ROS) (24). We and others have demonstrated induction of oxidative stress on exposure of vascular cell types to various HIV proteins, including Tat, and on exposure to illicit drugs, such as cocaine and opioids (11,25,26). Therefore, in this study, we explored the possibility of ROS-mediated ligand-independent activation of PDGFR in HPASMCs on combined treatment with cocaine and Tat.…”