title: Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice.
abstract: Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor alpha and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects.
authors.affiliation: Department of Cardiology and Pulmology, Charite-Universitätsmedizin Berlin, Campus Benjamin Franklin, Med Klinik II, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Sandra
authors.initials: S
authors.lastname: Bien
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Peter M
authors.initials: PM
authors.lastname: Becher
authors.forename: Komal
authors.initials: K
authors.lastname: Loya
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Heinz P
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007527:Isoenzymes; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D000077340:Fluvastatin; D004317:Doxorubicin; D013482:Superoxide Dismutase