Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice - PubMed (original) (raw)
Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice
Yukitaka Shizukuda et al. Mol Cell Biochem. 2005 May.
Abstract
Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6-8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31 +/- 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.
Similar articles
- Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy.
van Almen GC, Swinnen M, Carai P, Verhesen W, Cleutjens JP, D'hooge J, Verheyen FK, Pinto YM, Schroen B, Carmeliet P, Heymans S. van Almen GC, et al. J Mol Cell Cardiol. 2011 Sep;51(3):318-28. doi: 10.1016/j.yjmcc.2011.05.010. Epub 2011 May 23. J Mol Cell Cardiol. 2011. PMID: 21624372 - Loss of Mrp1 Potentiates Doxorubicin-Induced Cytotoxicity in Neonatal Mouse Cardiomyocytes and Cardiac Fibroblasts.
Zhang W, St Clair D, Butterfield A, Vore M. Zhang W, et al. Toxicol Sci. 2016 May;151(1):44-56. doi: 10.1093/toxsci/kfw021. Epub 2016 Jan 27. Toxicol Sci. 2016. PMID: 26822305 Free PMC article. - Loss of multidrug resistance-associated protein 1 potentiates chronic doxorubicin-induced cardiac dysfunction in mice.
Zhang W, Deng J, Sunkara M, Morris AJ, Wang C, St Clair D, Vore M. Zhang W, et al. J Pharmacol Exp Ther. 2015 Nov;355(2):280-7. doi: 10.1124/jpet.115.225581. Epub 2015 Sep 9. J Pharmacol Exp Ther. 2015. PMID: 26354995 Free PMC article. - Activation of the ubiquitin-proteasome system in doxorubicin cardiomyopathy.
Ranek MJ, Wang X. Ranek MJ, et al. Curr Hypertens Rep. 2009 Dec;11(6):389-95. doi: 10.1007/s11906-009-0068-8. Curr Hypertens Rep. 2009. PMID: 19895749 Free PMC article. Review. - p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act.
Guo Y, Tang Y, Lu G, Gu J. Guo Y, et al. Nutrients. 2023 May 10;15(10):2259. doi: 10.3390/nu15102259. Nutrients. 2023. PMID: 37242146 Free PMC article. Review.
Cited by
- Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases.
Luan Y, Yang Y, Luan Y, Liu H, Xing H, Pei J, Liu H, Qin B, Ren K. Luan Y, et al. J Zhejiang Univ Sci B. 2024 Jan 15;25(1):1-22. doi: 10.1631/jzus.B2300097. J Zhejiang Univ Sci B. 2024. PMID: 38163663 Free PMC article. Review. - TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage.
Yu W, Xu H, Sun Z, Du Y, Sun S, Abudureyimu M, Zhang M, Tao J, Ge J, Ren J, Zhang Y. Yu W, et al. Acta Pharm Sin B. 2023 Dec;13(12):4823-4839. doi: 10.1016/j.apsb.2023.09.008. Epub 2023 Sep 17. Acta Pharm Sin B. 2023. PMID: 38045047 Free PMC article. - Infiltrating macrophages amplify doxorubicin-induced cardiac damage: role of catecholamines.
Gambardella J, Santulli G, Fiordelisi A, Cerasuolo FA, Wang X, Prevete N, Sommella E, Avvisato R, Buonaiuto A, Altobelli GG, Rinaldi L, Chiuso F, Feliciello A, Dal Piaz F, Campiglia P, Ciccarelli M, Morisco C, Sadoshima J, Iaccarino G, Sorriento D. Gambardella J, et al. Cell Mol Life Sci. 2023 Oct 11;80(11):323. doi: 10.1007/s00018-023-04922-5. Cell Mol Life Sci. 2023. PMID: 37819449 Free PMC article. - Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.
Kwok C, Nolan M. Kwok C, et al. Front Cardiovasc Med. 2023 Sep 8;10:1150569. doi: 10.3389/fcvm.2023.1150569. eCollection 2023. Front Cardiovasc Med. 2023. PMID: 37745115 Free PMC article. Review. - Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling.
Peng K, Zeng C, Gao Y, Liu B, Li L, Xu K, Yin Y, Qiu Y, Zhang M, Ma F, Wang Z. Peng K, et al. Acta Pharm Sin B. 2023 Jun;13(6):2680-2700. doi: 10.1016/j.apsb.2023.03.019. Epub 2023 Mar 25. Acta Pharm Sin B. 2023. PMID: 37425037 Free PMC article.
References
- Am J Pathol. 1999 Feb;154(2):567-80 - PubMed
- N Engl J Med. 2004 Jul 8;351(2):145-53 - PubMed
- Nature. 1997 Sep 18;389(6648):300-5 - PubMed
- EMBO J. 1999 Nov 1;18(21):6027-36 - PubMed
- Circulation. 2000 Oct 24;102(17):2105-10 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous