The deleterious effects of doxorubicin were attenuated in p53 heterozygous knockout mice, indicating that p53 deposition plays a role in doxorubicin cardiotoxicity.. p53 induced cardiomyocyte apoptosis, myocardial ischemia, and mTOR inhibition have already been implicated in the pathogenesis of various types of heart failure. Nevertheless, doxorubicin cardiotoxicity was attenuated by cardiac certain overexpression of anti apoptotic protein Bcl 2, whereas myocardial boat occurrence o-r myocyte size was not modified by chronic doxorubicin therapy. Therefore, doxorubicin cardiotoxicity is mediated by Celecoxib COX inhibitor p53 dependent cardiomyocyte apoptosis. Because oxidative stress is really a important inducer of p53 accumulation in the center by doxorubicin and statins have demonstrated an ability to have antioxidant effects,we examinedwhether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pretreatment with pitavastatin attenuated doxorubicin induced cardiomyocyte death, ATM phosphorylation, p53 deposition, and oxidative stress and.. Statins are known to exert their fat lowering independent effects by inhibiting the synthesis of isoprenoids that are critical for posttranslational modification of a variety of proteins. We for that reason examined whether pitavastatin attenuates doxorubicin cardiotoxicity through the inhibition of mevalonate dependent posttranslational protein modifications. Pretreatment with mevalonate, FPP, or GGPP reversed the beneficial results of pitavastatin on doxorubicin induced oxidative stress and p53 accumulation.. Similarly, GTI although not FTI Metastasis reduced doxorubicin induced oxidative stress and p53 accumulation, indicating that the inhibition of protein geranylgeranylation mediates the cardioprotective effects of pitavastatin. Because Rac1 is really a important regulator of NADPH oxidase activity and activated by geranylgeranylation but not by farnesylation, we next examined the possible participation of Rac1 in pitavastatin mediated effects against doxorubicin. Indeed, treatment with a Rac1 chemical also attenuated doxorubicin induced p53 accumulation and oxidative stress to-the extent comparable with those of pitavastatin andGTI.. Eventually, treatment with pitavastatin somewhat attenuated long-term doxorubicin treatment induced cardiomyocyte apoptosis and contractile dysfunction in vivo, that is consistent with a current report by the others. In classy myocytes, doxorunbicin increased NADPH oxidase CHK1 inhibitor activity, which was attenuated both by a NADPH oxidase assembly inhibitor and a Rac1 inhibitor.. Furthermore, pitavastatin attenuated Rac1 activity as assessed by subcellular localization.. These results collectively suggest that pitavastatin attenuates doxorubicin cardiotoxicity through its antioxidant effect involving Rac1 inhibition. A few lines of evidence suggest that p53 accumulation and oxidative stress are involved in doxorubicin induced cardiotoxicity.