PT  - JOURNAL ARTICLE
AU  - Lampson Fan
AU  - David Sawbridge
AU  - Vinoj George
AU  - Lei Teng
AU  - Alexis Bailey
AU  - Ian Kitchen
AU  - Jian-Mei Li
TI  - Chronic Cocaine-Induced Cardiac Oxidative Stress and Mitogen-Activated Protein Kinase Activation: The Role of Nox2 Oxidase
AID  - 10.1124/jpet.108.145201
DP  - 2009 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 99--106
VI  - 328
IP  - 1
4099  - http://jpet.aspetjournals.org/content/328/1/99.short
4100  - http://jpet.aspetjournals.org/content/328/1/99.full
SO  - J Pharmacol Exp Ther2009 Jan 01; 328
AB  - Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating “binge” cocaine administration (milligrams per kilogram): days 1 to 4 at 3 × 15 mg, days 5 to 8 at 3 × 20 mg, days 9 to 12 at 3 × 25 mg, and days 13 to 14 at 3 × 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document} production (1.96- ± 0.4-fold) as detected by tiron (an \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document} scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases (∼2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22phox, p67phox, p47phox, p40phox, and Rac1, and in p47phox phosphorylation as detected by immunoblotting (all p < 0.03). Increased Nox2 activity was accompanied by the activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH2-terminal kinase, notably in the cardiomyocytes. Cell culture experiments revealed that cocaine-induced ROS production was primarily a direct action of cocaine on cardiac myocytes, which caused severe oxidative damage to myocytes and cell death as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. These could be inhibited by inhibitors to protein kinase C (bisindolymaleimide) or by depletion of Nox2 using small interfering RNA. In conclusion, chronic cocaine administration directly causes severe myocardial oxidative stress through the activation of Nox2 oxidase. Increased ROS production contributes to MAPK activation and the subsequent myocyte damage. Inhibitors to NADPH oxidase or antioxidants may have therapeutic potential in the treatment of cocaine cardiotoxicity. The American Society for Pharmacology and Experimental Therapeutics