Parthenolide induces a distinct pattern of oxidative stress in cardiac myocytes.
Although parthenolide was reported to reduce cardiovascular damage in endotoxic shock and have beneficial effects in myocardial ischemia, its actions on cardiac myocytes have not been reported. Because parthenolide possesses an alpha-methylene-gamma-lactone ring and epoxide residue, we hypothesized that it would induce oxidative stress in cardiac myocytes. Superoxide production and sources, viability, glutathione levels, and mitochondrial membrane potential were studied in neonatal rat ventricular myocytes treated with parthenolide. Parthenolide, dose dependently, induced oxidase activity as assessed by superoxide generation in cell lysates. Superoxide formation was increased more than 4-fold with 50 microM parthenolide. At concentrations >5 microM, parthenolide decreased cell viability in a dose-and time-dependent manner, and activated the stress MAP kinases JNK and p38. Over 6 h, parthenolide at concentrations >5 microM markedly depleted intracellular glutathione and led to collapse of the mitochondrial membrane potential. At lower parthenolide concentrations (<5 microM) the source of superoxide was mitochondria; at higher concentrations (>5 microM) the primary source was NADPH oxidase. We conclude that parthenolide causes oxidative stress in cardiac myocytes by inducing superoxide formation by mitochondrial and NADPH oxidase in a dose-dependent manner. Parthenolide may be a useful tool for studying the roles of oxidative stress and mitochondrial dysfunction in the pathogenesis of cardiac hypertrophy and failure.
Kurdi
Mazen
M
Division of Molecular Cardiology, Texas A&M University System Health Science Center, Temple, TX, USA.
Bowers
Mark C
MC
Dado
Joana
J
Booz
George W
GW
D000818:Animals; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D008564:Membrane Potentials; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; C002669:parthenolide; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione