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The Fig 5. Involvement of p53 in the modify in IGF-1R /Deforolimus structure IGFBP-three amounts brought on by doxorubicin. (A) Representative western blot and band densitometry for p53 24 hours after no therapy (Ctr) or incubation of H9c2 cardiomyocytes with .one, .five, or one M doxorubicin (Dox). (B and C) IGF-1R/IGFBP-three expression (band densitometry and representative western blot, B) and annexin V/propidium iodide positivity (C) in H9c2 cardiomyocytes untreated or uncovered to 1 M Dox with or without pre-therapy with PFT-. , P <0.05 vs. Ctr , P <0.001 vs. Ctr. ^, P <0.01 vs. Dox 1.responsiveness to IGF-1 appears to be compromised as a result of the down-regulation of IGF1R, through which IGF-1 acts, and the up-regulation of IGFBP-3, which instead reduces the amount of IGF-1 available to interact with IGF-1R. Of note, IGFBP-3 can also cause apoptosis via IGF-1 independent mechanisms [27]. The variations in IGF-1R and IGFBP-3 are at least in part due to the accumulation and activation of p53, a key player in cardiac cell apoptosis prompted by anthracyclines. Indeed, upon exposure to doxorubicin the hearts of p53 knockout mice display significantly less apoptotic cells than their wild-type counterparts [28] and in our experiments p53 inhibition by PFT- antagonized doxorubicin-induced apoptosis (Fig 5). Therefore, we hypothesize that the loss of sensitivity to IGF-1 and the increase in IGFBP-3 production are effectors of p53-dependent cardiomyocyte apoptosis elicited by anthracyclines. Historically, it has been postulated that generation of reactive oxygen species (ROS) is the most upstream event in the cascade of intracellular alterations underlying anthracycline cardiotoxicity [1] and there have been reports that p53 induction is secondary to oxidative stress in cardiomyocytes treated with doxorubicin [22,29]. However, recent research work suggests that blockade of the activity of topoisomerase-II is at the origin of anthracycline damage to cardiomyocytes [30] and is followed by p53 activation on the one side and ROS formation on the Fig 6. Antioxidants reverse doxorubicin-initiated apoptosis and IGF-1R /IGFBP-3 perturbation. Frequency of apoptotic cells (A) and IGF-1R and IGFBP-3 expression (representative western blot in B and densitometry of western blot bands in C) 24 hours after no treatment (Ctr) or incubation of H9c2 cardiomyocytes with 1 M doxorubicin (Dox) with or without pre-treatment with N-acetylcysteine (NAC), dexrazoxane (DEX), or carvedilol (CARV). , P <0.05 vs. Ctr , P <0.01 vs. Ctr , P <0.001 vs. Ctr , P <0.0001 vs. Ctr. , P <0.05 vs. Dox 1 ^, P <0.01 vs. Dox 1.other one, the two phenomena enhancing each other [31]. Thus, our finding that pre-treatment with anti-oxidants abrogated doxorubicin effect on IGF-1R and IGFBP-3 expression may be ascribed to the induction of p53, but also to some oxidative stress-dependent, p53-independent pathway(s). This may be particularly true for the modulation of IGF-1R, which was completely prevented by anti-oxidants, but not by PFT- (Figs 5 and 6). Importantly, IGF-1 exerts other actions on cardiomyocytes and CPCs, such as stimulation of hypertrophy [32] and proliferation [5], respectively, that support the1310013 adaptation of the heart to injury. Although not assessed in this study, these cardioprotective effects are also likely to be hindered by doxorubicin. Unlike Igf1r and Igfbp3, Igf1 was not expressed by both unstimulated and doxorubicin-treated H9c2 cells.

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Author: Cholesterol Absorption Inhibitors