RT Journal Article
SR Electronic
T1 Vesnarinone Causes Oxidative Damage by Inhibiting Catalase Function through Ceramide Action in Myeloid Cell Apoptosis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 620
OP 627
DO 10.1124/mol.61.3.620
VO 61
IS 3
A1 Tadakazu Kondo
A1 Yoshiko Suzuki
A1 Toshiyuki Kitano
A1 Kazuya Iwai
A1 Mitsumasa Watanabe
A1 Hisanori Umehara
A1 Naoharu Daido
A1 Naochika Domae
A1 Masaro Tashima
A1 Takashi Uchiyama
A1 Toshiro Okazaki
YR 2002
UL http://molpharm.aspetjournals.org/content/61/3/620.abstract
AB Vesnarinone is an effective inotropic agent for treating congestive heart failure, but its clinical usage is restricted because of the severe side effect of agranulocytosis. In myeloid HL-60 cells, vesnarinone increased the intracellular content of a proapoptotic lipid mediator, ceramide, in a time- and dose-dependent manner. Vesnarinone-induced apoptosis was significantly enhanced by simultaneous treatment with a cell-permeable N-acetyl sphingosine (C2-ceramide). Treatment with neither vesnarinone, C2-ceramide, nor simultaneously with vesnarinone and C2-ceramide caused a marked increase of reactive oxygen intermediates (ROI) generation measured by the 2′,7′-dichlorofluorescin method. However, oxidative damage judged by the production of lipid peroxidates and the nitroblue tetrazolium-reducing ability were enhanced more significantly by simultaneous treatment with vesnarinone and C2-ceramide than by vesnarinone alone. Moreover, vesnarinone inhibited catalase function both at the protein and activity level, and this inhibition was synergistically enhanced by C2-ceramide, and vesnarinone-induced oxidative damage and apoptosis were significantly suppressed by treatment of HL-60 cells with purified catalase. C2-ceramide enhanced vesnarinone-induced inhibition of the ROI-scavenging enzyme catalase at the levels of protein and activity in HL-60 cells; in contrast, however, vesnarinone did not induce ceramide generation, oxidative damage, or catalase depletion in HL-60/ves cells, where vesnarinone could not induce apoptosis. Taken together, the results suggest that vesnarinone induces myeloid cell apoptosis by increasing oxidative damage via ceramide-induced inhibition of catalase function.